Dusty Disks Around Central Stars of Planetary Nebulae

Only a few percent of cool, old white dwarfs (WDs) have infrared excesses interpreted as originating in small hot disks due to the infall and destruction of single asteroids that come within the star's Roche limit. Infrared excesses at 24 micron were also found to derive from the immediate vicinity of younger, hot WDs, most of which are still central stars of planetary nebulae (CSPN). The incidence of CSPN with this excess is 18%. The Helix CSPN, with a 24 micron excess, has been suggested to have a disk formed from collisions of Kuiper belt-like objects (KBOs). In this paper, we have analyzed an additional sample of CSPN to look for similar infrared excesses. These CSPN are all members of the PG 1159 class and were chosen because their immediate progenitors are known to often have dusty environments consistent with large dusty disks. We find that, overall, PG 1159 stars do not present such disks more often than other CSPN, although the statistics (5 objects) are poor. We then consider the entire sample of CSPN with infrared excesses, and compare it to the infrared properties of old WDs, as well as cooler post-AGB stars. We conclude with the suggestion that the infrared properties of CSPN more plausibly derive from AGB-formed disks rather than disks formed via the collision of KBOs, although the latter scenario cannot be ruled out. We finally remark that there seems to be an association between CSPN with a 24 micron excess and confirmed or possible binarity of the central star.Comment: 11 pages, 5 figures, AJ, in pres

Association of β-Amyloid Burden With Sleep Dysfunction and Cognitive Impairment in Elderly Individuals With Cognitive Disorders.

Importance: Evidence shows that sleep dysfunction and β-amyloid (Aβ) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aβ continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective: To determine whether Aβ deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants: A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures: Sleep quality was measured via responses to sleep questionnaires, Aβ deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results: Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aβ deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aβ deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P \u3c .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P \u3c .001). Mediation analysis demonstrated an indirect association between Aβ deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance: Nighttime sleep disruption may mediate the association between Aβ and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aβ burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aβ accumulation

ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer\u27s Disease.

Alzheimer\u27s disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ΔFosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ΔFosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering histone deacetylation. Acute histone deacetylase (HDAC) inhibition or inhibition of ΔFosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in ΔFosB-mediated suppression of c-Fos, suggesting that this mechanism is not confined to AD mice. These results explain observations that c-Fos expression increases after acute neuronal activity but decreases with chronic activity. Moreover, these results indicate a general mechanism by which seizures contribute to persistent cognitive deficits, even during seizure-free periods

Epigenetic suppression of hippocampal calbindin-D28k by ΔFosB drives seizure-related cognitive deficits.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer\u27s disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that ΔFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of ΔFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of ΔFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by ΔFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures

Ranitidine Use and Incident Cancer in a Multinational Cohort

Importance: Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. Objective: To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. Design, Setting, and Participants: This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. Exposure: The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). Main Outcomes and Measures: The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. Results: Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. Conclusions and Relevance: In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.</p

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.

Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity

Premature Discontinuation of Pediatric Randomized Controlled Trials : A Retrospective Cohort Study

Objectives To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. Study design A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. Results We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). Conclusion Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.Peer reviewe

Tension and Robustness in Multitasking Cellular Networks

Cellular networks multitask by exhibiting distinct, context-dependent dynamics. However, network states (parameters) that generate a particular dynamic are often sub-optimal for others, defining a source of “tension” between them. Though multitasking is pervasive, it is not clear where tension arises, what consequences it has, and how it is resolved. We developed a generic computational framework to examine the source and consequences of tension between pairs of dynamics exhibited by the well-studied RB-E2F switch regulating cell cycle entry. We found that tension arose from task-dependent shifts in parameters associated with network modules. Although parameter sets common to distinct dynamics did exist, tension reduced both their accessibility and resilience to perturbation, indicating a trade-off between “one-size-fits-all” solutions and robustness. With high tension, robustness can be preserved by dynamic shifting of modules, enabling the network to toggle between tasks, and by increasing network complexity, in this case by gene duplication. We propose that tension is a general constraint on the architecture and operation of multitasking biological networks. To this end, our work provides a framework to quantify the extent of tension between any network dynamics and how it affects network robustness. Such analysis would suggest new ways to interfere with network elements to elucidate the design principles of cellular networks