The cysteine protease ATG4B is a key component of the autophagy machinery, acting to proteolytically prime and recycle its substrate MAP1LC3B. The roles of ATG4B in cancer and other diseases appear ...to be context dependent but are still not well understood. To help further explore ATG4B functions and potential therapeutic applications, we employed a chemical biology approach to identify ATG4B inhibitors. Here, we describe the discovery of 4-28, a styrylquinoline identified by a combined computational modeling, in silico screening, high content cell-based screening and biochemical assay approach. A structure-activity relationship study led to the development of a more stable and potent compound LV-320. We demonstrated that LV-320 inhibits ATG4B enzymatic activity, blocks autophagic flux in cells, and is stable, non-toxic and active in vivo. These findings suggest that LV-320 will serve as a relevant chemical tool to study the various roles of ATG4B in cancer and other contexts.
Titan was once thought to have global oceans of light hydrocarbons on its surface, but after 40 close flybys of Titan by the Cassini spacecraft, it has become clear that no such oceans exist. There ...are, however, features similar to terrestrial lakes and seas, and widespread evidence for fluvial erosion, presumably driven by precipitation of liquid methane from Titan's dense, nitrogen-dominated atmosphere. Here we report infrared spectroscopic data, obtained by the Visual and Infrared Mapping Spectrometer (VIMS) on board the Cassini spacecraft, that strongly indicate that ethane, probably in liquid solution with methane, nitrogen and other low-molecular-mass hydrocarbons, is contained within Titan's Ontario Lacus.
To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD).
We administered a neuropsychological battery and the University of ...Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age- and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment MCI, dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed.
Demographics, UPSIT, and Unified Parkinson's Disease Rating Scale-III performance did not differ between GBA carriers and noncarriers. GBA mutation carriers performed more poorly than noncarriers on the Mini-Mental State Examination (p = 0.035), and on the memory (p = 0.017) and visuospatial (p = 0.028) domains. The most prominent differences were observed in nonverbal memory performance (p < 0.001). Carriers were more likely to receive scores of 0.5 or higher on the CDR (p < 0.001), and a clinical diagnosis of either MCI or dementia (p = 0.004).
GBA mutation status may be an independent risk factor for cognitive impairment in patients with PD.
Objective No studies exist that have examined the effectiveness of different approaches to a reduction in elective early term deliveries or the effect of such policies on newborn intensive care ...admissions and stillbirth rates. Study Design We conducted a retrospective cohort study of prospectively collected data and examined outcomes in 27 hospitals before and after implementation of 1 of 3 strategies for the reduction of elective early term deliveries. Results Elective early term delivery was reduced from 9.6-4.3% of deliveries, and the rate of term neonatal intensive care admissions fell by 16%. We observed no increase in still births. The greatest improvement was seen when elective deliveries at <39 weeks were not allowed by hospital personnel. Conclusion Physician education and the adoption of policies backed only by peer review are less effective than “hard stop” hospital policies to prevent this practice. A 5% rate of elective early term delivery would be reasonable as a national quality benchmark.
Abstract Background Lowering dietary sodium and adhering to medication regimens are difficult for persons with heart failure (HF). Because these behaviors often occur within the family context, this ...study evaluated the effects of family education and partnership interventions on dietary sodium (Na) intake and medication adherence (MA). Methods and Results HF patient and family member (FM) dyads (n = 117) were randomized to: usual care (UC), patient-FM education (PFE), or family partnership intervention (FPI). Dietary Na (3-day food record), urinary Na (24-hour urine), and MA (Medication Events Monitoring System) were measured at baseline (BL) before randomization, and at 4 and 8 months. FPI and PFE reduced urinary Na at 4 months, and FPI differed from UC at 8 months ( P = .016). Dietary Na decreased from BL to 4 months, with both PFE ( P = .04) and FPI ( P = .018) lower than UC. The proportion of subjects adherent to Na intake (≤2,500 mg/d) was higher at 8 months in PFE and FPI than in UC (χ2(2) = 7.076; P = .029). MA did not differ among groups across time. Both FPI and PFE groups increased HF knowledge immediately after intervention. Conclusions Dietary Na intake, but not MA, was improved by PFE and FPI compared with UC. The UC group was less likely to be adherent with dietary Na. Greater efforts to study and incorporate family-focused education and support interventions into HF care are warranted.
The VLT-FLAMES Tarantula Survey Sana, H; de Koter, A; de Mink, S E ...
Astronomy and astrophysics (Berlin),
02/2013, Letnik:
550
Journal Article
Recenzirano
Odprti dostop
The Tarantula Nebula in the Large Magellanic Cloud is our closest view of a starburst region and is the ideal environment to investigate important questions regarding the formation, evolution and ...final fate of the most massive stars. We analyze the multiplicity properties of the massive O-type star population observed through multi-epoch spectroscopy in the framework of the VLT-FLAMES Tarantula Survey. With 360 O-type stars, this is the largest homogeneous sample of massive stars analyzed to date. Using the multiplicity properties of the O stars in the Tarantula region and simple evolutionary considerations, we estimate that over 50% of the current O star population will exchange mass with its companion within a binary system. This shows that binary interaction is greatly affecting the evolution and fate of massive stars, and must be taken into account to correctly interpret unresolved populations of massive stars.
Objective The purpose of this study was to examine the efficacy of specific protocols that have been developed in response to a previous analysis of maternal deaths in a large hospital system. We ...also analyzed the theoretic impact of an ideal system of maternal triage and transport on maternal deaths and the relative performance of cause of death determination from chart review compared with a review of discharge coding data. Study Design We conducted a retrospective evaluation of maternal deaths from 2007-2012 after the introduction of disease-specific protocols that were based on 2000-2006 data. Results Our maternal mortality rate was 6.4 of 100,000 births in just >1.2 million deliveries. A policy of universal use of pneumatic compression devices for all women who underwent cesarean delivery resulted in a decrease in postoperative pulmonary embolism deaths from 7 of 458,097 cesarean births to 1 of 465,880 births ( P = .038). A policy that involved automatic and rapid antihypertensive therapy for defined blood pressure thresholds eliminated deaths from in-hospital intracranial hemorrhage and reduced overall deaths from preeclampsia from 15-3 ( P = .02.) From 1-3 deaths were related causally to cesarean delivery. Only 7% of deaths were potentially preventable with an ideal system of admission triage and transport. Cause of death analysis with the use of discharge coding data was correct in 52% of cases. Conclusion Disease-specific protocols are beneficial in the reduction of maternal death because of hypertensive disease and postoperative pulmonary embolism. From 2-6 women die annually in the United States because of cesarean delivery itself. A reduction in deaths from postpartum hemorrhage should be the priority for maternal death prevention efforts in coming years in the United States.
Abstract For 30 years, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network has had significant impact on clinical ...practice in obstetrics. The MFMU Network has conducted 50 randomized clinical trials and observational studies designed to improve pregnancy outcomes for mothers and children. Each center has a designated clinical research nurse coordinator who coordinates the day-to-day operations of each trial and leads a research team that is responsible for recruitment and retention of participants. Some of the lessons learned by the nurse coordinators over the past 30 years are described with examples from recent studies. Best practices that we have amassed from our experience are also described.
The Antarctic Ice Sheet (AIS) response to past warming consistent with the 1.5–2°C “safe limit” of the United Nations Paris Agreement is currently not well known. Empirical evidence from the most ...recent comparable period, the Last Interglaciation, is sparse, and transient ice‐sheet experiments are few and inconsistent. Here, we present new, transient, GCM‐forced ice‐sheet simulations validated against proxy reconstructions. This is the first time such an evaluation has been attempted. Our empirically constrained simulations indicate that the AIS contributed 4 m to global mean sea level by 126 ka BP, with ice lost primarily from the Amundsen, but not Ross or Weddell Sea, sectors. We resolve the conflict between previous work and show that the AIS thinned in the Wilkes Subglacial Basin but did not retreat. We also find that the West AIS may be predisposed to future collapse even in the absence of further environmental change, consistent with previous studies.
Plain Language Summary
Ice sheets can respond to climatic warming in complex ways, commonly only reaching a new state of balance many hundreds or even thousands of years after the initial change in climate has occurred. Here, we investigate how the Antarctic Ice Sheet (AIS) responded to a period of prolonged warmer‐than‐present climate that took place around 125,000 years ago. At this time the global climate was only around 1–2°C above present, but geological records show that the global sea level was at least 6 m, or maybe even as much as 9–11 m, higher than today. Our study shows that around 4 m of this could have come from Antarctica. Our model agrees well with geological evidence of enhanced ice discharge both close to the ice sheet and further afield. Applying this model to the future our experiments suggest that the West AIS may already have been sufficiently destabilized to trigger a long‐term sea‐level contribution of up to 4 m, even without further greenhouse gas emissions.
Key Points
We present data‐constrained simulations of the Antarctic Ice Sheet through the Last Interglaciation
Our model predicts a maximum contribution to global mean sea level of 4 m at 126 ka BP
Loss of much of the present‐day West Antarctic Ice Sheet is already committed under current climate
PDF
