Degeneration of central cholinergic neurons impairs memory, and enhancement of cholinergic synapses improves cognitive processes. Cholinergic signaling is also anti-inflammatory, and ...neuroinflammation is increasingly linked to adverse memory, especially in Alzheimer's disease. Much of the evidence surrounding cholinergic impacts on the neuroimmune system focuses on the α7 nicotinic acetylcholine (ACh) receptor, as stimulation of this receptor prevents many of the effects of immune activation. Microglia and astrocytes both express this receptor, so it is possible that some cholinergic effects may be
these non-neuronal cells. Though the presence of microglia is required for memory, overactivated microglia due to an immune challenge overproduce inflammatory cytokines, which is adverse for memory. Blocking these exaggerated effects, specifically by decreasing the release of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), has been shown to prevent inflammation-induced memory impairment. While there is considerable evidence that cholinergic signaling improves memory, fewer studies have linked the "cholinergic anti-inflammatory pathway" to memory processes. This review will summarize the current understanding of the cholinergic anti-inflammatory pathway as it relates to memory and will argue that one mechanism by which the cholinergic system modulates hippocampal memory processes is its influence on neuroimmune function
the α7 nicotinic ACh receptor.
Colorectal cancer (CRC) incidence and mortality are increasing among persons younger than 50 years old in the United States, but risk factors associated with early-onset CRC (EOCRC) have not been ...widely studied.
We conducted a case-control study of US veterans 18 to 49 years old who underwent colonoscopy examinations from 1999 through 2014. EOCRC cases were identified from a national cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of follow-up were identified as controls. We collected data on age, sex, race/ethnicity, body weight, body mass index (BMI), diabetes, smoking status, and aspirin use. Multivariate-adjusted EOCRC odds were estimated for each factor, with corresponding 95% confidence interval (CI) values.
Our final analysis included 651 EOCRC cases and 67,416 controls. Median age was 45.3 years, and 82.3% were male. Higher proportions of cases were older, male, current smokers, nonaspirin users, and had lower BMIs, compared with controls (P < .05). In adjusted analyses, increasing age and male sex were significantly associated with increased risk of EOCRC, whereas aspirin use and being overweight or obese (relative to normal BMI) were significantly associated with decreased odds of EOCRC. In post hoc analyses, weight loss of 5 kg or more within the 5-year period preceding colonoscopy was associated with higher odds of EOCRC (odds ratio 2.23; 95% CI 1.76–2.83).
In a case-control study of veterans, we found increasing age and male sex to be significantly associated with increased risk of EOCRC, and aspirin use to be significantly associated with decreased risk; these factors also affect risk for CRC onset after age 50. Weight loss may be an early clinical sign of EOCRC. More intense efforts are required to identify the factors that cause EOCRC and signs that can be used to identify individuals at highest risk.
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ABSTRACT
The James Webb Space Telescope (JWST) is expected to observe galaxies at z > 10 that are presently inaccessible. Here, we use a self-consistent empirical model, the universemachine, to ...generate mock galaxy catalogues and light-cones over the redshift range z = 0−15. These data include realistic galaxy properties (stellar masses, star formation rates, and UV luminosities), galaxy–halo relationships, and galaxy–galaxy clustering. Mock observables are also provided for different model parameters spanning observational uncertainties at z < 10. We predict that Cycle 1 JWST surveys will very likely detect galaxies with M* > 107 M⊙ and/or M1500 < −17 out to at least z ∼ 13.5. Number density uncertainties at z > 12 expand dramatically, so efforts to detect z > 12 galaxies will provide the most valuable constraints on galaxy formation models. The faint-end slopes of the stellar mass/luminosity functions at a given mass/luminosity threshold steepen as redshift increases. This is because observable galaxies are hosted by haloes in the exponentially falling regime of the halo mass function at high redshifts. Hence, these faint-end slopes are robustly predicted to become shallower below current observable limits (M* < 107 M⊙ or M1500 > −17). For reionization models, extrapolating luminosity functions with a constant faint-end slope from M1500 = −17 down to M1500 = −12 gives the most reasonable upper limit for the total UV luminosity and cosmic star formation rate up to z ∼ 12. We compare to three other empirical models and one semi-analytic model, showing that the range of predicted observables from our approach encompasses predictions from other techniques. Public catalogues and light-cones for common fields are available online.
We report the serendipitous detection of two 3 mm continuum sources found in deep ALMA Band 3 observations to study intermediate-redshift galaxies in the COSMOS field. One is near a foreground galaxy ...at 1 3, but is a previously unknown dust-obscured star-forming galaxy (DSFG) at probable zCO = 3.329, illustrating the risk of misidentifying shorter wavelength counterparts. The optical-to-millimeter spectral energy distribution (SED) favors a gray λ−0.4 attenuation curve and results in significantly larger stellar mass and SFR compared to a Calzetti starburst law, suggesting caution when relating progenitors and descendants based on these quantities. The other source is missing from all previous optical/near-infrared/submillimeter/radio catalogs ("ALMA-only"), and remains undetected even in stacked ultradeep optical (>29.6 AB) and near-infrared (>27.9 AB) images. Using the ALMA position as a prior reveals faint signal-to-noise ratio ∼ 3 measurements in stacked IRAC 3.6+4.5, ultradeep SCUBA2 850 m, and VLA 3 GHz, indicating the source is real. The SED is robustly reproduced by a massive M* = 1010.8M and Mgas = 1011M , highly obscured AV ∼ 4, star-forming SFR ∼ 300 M yr−1 galaxy at redshift z = 5.5 1.1. The ultrasmall 8 arcmin2 survey area implies a large yet uncertain contribution to the cosmic star formation rate density CSFRD(z = 5) ∼ 0.9 × 10−2 M yr−1 Mpc−3, comparable to all ultraviolet-selected galaxies combined. These results indicate the existence of a prominent population of DSFGs at z > 4, below the typical detection limit of bright galaxies found in single-dish submillimeter surveys, but with larger space densities ∼3 × 10−5 Mpc−3, higher duty cycles of 50%-100%, contributing more to the CSFRD, and potentially dominating the high-mass galaxy stellar mass function.
Until recently, multi-agent chemotherapy (CT) was the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Clinical trials have confirmed benefits in overall survival (OS) ...and progression-free survival with immunotherapy (IO) compared to CT. This study compares real-world treatment patterns and outcomes between CT and IO administrations in second-line (2L) settings for patients with stage IV NSCLC.
This retrospective study included patients in the United States Department of Veterans Affairs healthcare system diagnosed with stage IV NSCLC during 2012-2017 and receiving IO or CT in the 2L. Patient demographics and clinical characteristics, healthcare resource utilization (HCRU), and adverse events (AEs) were compared between treatment groups. Logistic regression was used to examine differences in baseline characteristics between groups, and inverse probability weighting multivariable Cox proportional hazard regression was used to analyze OS.
Among 4,609 Veterans who received first-line (1L) therapy for stage IV NSCLC, 96% received 1L CT alone. A total of 1,630 (35%) were administered 2L systemic therapy, with 695 (43%) receiving IO and 935 (57%) receiving CT. Median age was 67 years (IO group) and 65 years (CT group); most patients were male (97%) and white (76-77%). Patients administered 2L IO had a higher Charlson Comorbidity Index than those administered CT (p = 0.0002). 2L IO was associated with significantly longer OS compared with CT (hazard ratio 0.84, 95% CI 0.75-0.94). IO was more frequently prescribed during the study period (p < 0.0001). No difference in rate of hospitalizations was observed between the two groups.
Overall, the proportion of advanced NSCLC patients receiving 2L systemic therapy is low. Among patients treated with 1L CT and without IO contraindications, 2L IO should be considered, as this supports potential benefit of IO for advanced NSCLC. The increasing availability and indications for IO will likely increase the administration of 2L therapy to NSCLC patients.
Abstract
We present Atacama Large Millimeter/submillimeter Array (ALMA) CO(2–1) spectroscopy of six massive (log
10
/
> 11.3) quiescent galaxies at
z
∼ 1.5. These data represent the largest sample ...using CO emission to trace molecular gas in quiescent galaxies above
z
> 1, achieving an average 3
σ
sensitivity of
∼ 10
10
. We detect one galaxy at 4
σ
significance and place upper limits on the molecular gas reservoirs of the other five, finding molecular gas mass fractions
(3
σ
upper limits). This is 1–2 orders of magnitude lower than coeval star-forming galaxies at similar stellar mass, and comparable to galaxies at
z
= 0 with similarly low specific star formation rate (sSFR). This indicates that their molecular gas reservoirs were rapidly and efficiently used up or destroyed, and that gas fractions are uniformly low (<6%) despite the structural diversity of our sample. The implied rapid depletion time of molecular gas (
< 0.6 Gyr) disagrees with extrapolations of empirical scaling relations to low sSFR. We find that our low gas fractions are instead in agreement with predictions from both the recent
simba
cosmological simulation, and from analytical “bathtub” models for gas accretion onto galaxies in massive dark matter halos (log
at
z
= 0). Such high mass halos reach a critical mass of log
by
z
∼ 4 that halt the accretion of baryons early in the universe. Our data are consistent with a simple picture where galaxies truncate accretion and then consume the existing gas at or faster than typical main-sequence rates. Alternatively, we cannot rule out that these galaxies reside in lower mass halos, and low gas fractions may instead reflect either stronger feedback, or more efficient gas consumption.
One of the greatest challenges to theoretical models of massive galaxy formation is the regulation of star formation at early times. The relative roles of molecular gas expulsion, depletion, and ...stabilization are uncertain as direct observational constraints of the gas reservoirs in quenched or quenching galaxies at high redshift are scant. We present ALMA observations of CO(2-1) in a massive ( ), recently quenched galaxy at z = 1.522. The optical spectrum of this object shows strong Balmer absorption lines, which implies that star formation ceased ∼0.8 Gyr ago. We do not detect CO(2-1) line emission, placing an upper limit on the molecular gas mass of . The implied gas fraction is , lower than typical star-forming galaxies at similar stellar masses at this redshift, among the lowest gas fractions at this specific star formation rate at any epoch, and the most stringent constraint on the gas contents of a passive galaxy to date. Our observations show that the depletion of from the interstellar medium of quenched objects can be both efficient and fairly complete, in contrast to recent claims of significant cold gas in recently quenched galaxies. We explore the variation in observed gas fractions in high-z galaxies and show that galaxies with high stellar surface density have low , similar to recent correlations between specific star formation rate and stellar surface density.
We present high spatial resolution imaging of the CO(1-0) line from the Karl G. Jansky Very Large Array of COSMOS 27289, a massive, compact star-forming galaxy (SFG) at z = 2.234. This galaxy was ...selected because of its structural similarity to z ∼ 2 passive galaxies. Our previous observations showed that it is very gas poor with respect to typical SFGs at these redshifts, consistent with a rapid transition to quiescence as the molecular gas is depleted. The new data show that both the molecular gas fraction, , and the molecular gas depletion time, /SFR, are lower in the central 1-2 kpc of the galaxy and rise at larger radii ∼2-4 kpc. These observations are consistent with a scenario in which COSMOS 27289 will imminently cease star formation in the inner regions before the outskirts, i.e., inside-out quenching, the first time this phenomenon has been seen via observations of molecular gas in the high-redshift universe. We find good qualitative and quantitative agreement with a hydrodynamical simulation of galaxy quenching, in which the central suppression of molecular gas arises due to rapid gas consumption and outflows that evacuate the central regions of gas. Our results provide independent evidence for inside-out quenching of star formation as a plausible formation mechanism for z ∼ 2 quiescent galaxies.
We report the detection of morphology-dependent stellar age in massive quenched galaxies (QGs) at z ∼ 1.2. The sense of the dependence is that compact QGs are 0.5-2 Gyr older than normal-sized ones. ...The evidence comes from three different age indicators- D n 4000 , H δ , and fits to spectral synthesis models-applied to their stacked optical spectra. All age indicators consistently show that the stellar populations of compact QGs are older than those of their normal-sized counterparts. We detect weak O ii emission in a fraction of QGs, and the strength of the line, when present, is similar between the two samples; however, compact galaxies exhibit a significantly lower frequency of O ii emission than normal ones. Fractions of both samples are individually detected in 7 Ms Chandra X-ray images (luminosities ∼1040-1041 erg s−1). The 7 Ms stacks of nondetected galaxies show similarly low luminosities in the soft band only, consistent with a hot gas origin for the X-ray emission. While both O ii emitters and nonemitters are also X-ray sources among normal galaxies, no compact galaxy with O ii emission is an X-ray source, arguing against an active galactic nucleus (AGN) powering the line in compact galaxies. We interpret the O ii properties as further evidence that compact galaxies are older and further along in the process of quenching star formation and suppressing gas accretion. Finally, we argue that the older age of compact QGs is evidence of progenitor bias: compact QGs simply reflect the smaller sizes of galaxies at their earlier quenching epoch, with stellar density most likely having nothing directly to do with cessation of star formation.
Star formation in half of massive galaxies was quenched by the time the Universe was 3 billion years old.sup.1. Very low amounts of molecular gas seem to be responsible for this, at least in some ...cases.sup.2-7, although morphological gas stabilization, shock heating or activity associated with accretion onto a central supermassive black hole are invoked in other cases.sup.8-11. Recent studies of quenching by gas depletion have been based on upper limits that are insufficiently sensitive to determine this robustly.sup.2-7, or stacked emission with its problems of averaging.sup.8,9. Here we report 1.3 mm observations of dust emission from 6 strongly lensed galaxies where star formation has been quenched, with magnifications of up to a factor of 30. Four of the six galaxies are undetected in dust emission, with an estimated upper limit on the dust mass of 0.0001 times the stellar mass, and by proxy (assuming a Milky Way molecular gas-to-dust ratio) 0.01 times the stellar mass in molecular gas. This is two orders of magnitude less molecular gas per unit stellar mass than seen in star forming galaxies at similar redshifts.sup.12-14. It remains difficult to extrapolate from these small samples, but these observations establish that gas depletion is responsible for a cessation of star formation in some fraction of high-redshift galaxies.
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