Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function ...correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC50 = 0.002 μM, cellular EC50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.
Objectives The aim of this study was to compare the reproducibility of 7 late gadolinium enhancement (LGE) quantification techniques across 3 conditions in which LGE is known to be important: acute ...myocardial infarction (AMI), chronic myocardial infarction (CMI), and hypertrophic cardiomyopathy (HCM). Background LGE by cardiac magnetic resonance is the gold-standard technique for assessing myocardial scar. No consensus exists on the best method for its quantification, and research in this area is scant. Techniques include manual quantification, thresholding by 2, 3, 4, 5, or 6 SDs above remote myocardium, and the full width at half maximum (FWHM) technique. To date, LGE has been linked to outcome in 3 conditions: AMI, CMI, and HCM. Methods Sixty patients with 3 LGE etiologies (AMI, n = 20; CMI, n = 20; HCM, n = 20) were scanned for LGE. LGE volume was quantified using the 7 techniques. Mean LGE volume, interobserver and intraobserver reproducibility, and impact on sample size were assessed. Results LGE volume varied significantly with the quantification method used. There was no statistically significant difference between LGE volume by the FWHM, manual, and 6-SD or 5-SD techniques. The 2-SD technique generated LGE volumes up to 2 times higher than the FWHM, 6-SD, and manual techniques. The reproducibility of all techniques was worse in HCM than AMI or CMI. The FWHM technique was the most reproducible in all 3 conditions compared with any other method (p < 0.001). Use of the FWHM technique for LGE quantification in paired analysis would lead to at least a 60% reduction in required sample size compared with any other method. Conclusions Regardless of the disease under study, the FWHM technique for LGE quantification gives LGE volume mean results similar to manual quantification and is statistically the most reproducible, reducing required sample sizes by up to one-half.
The practice of conservation occurs within complex socioecological systems fraught with challenges that require transparent, defensible, and often socially engaged project planning and management. ...Planning and decision support frameworks are designed to help conservation practitioners increase planning rigor, project accountability, stakeholder participation, transparency in decisions, and learning. We describe and contrast five common frameworks within the context of six fundamental questions (why, who, what, where, when, how) at each of three planning stages of adaptive management (project scoping, operational planning, learning). We demonstrate that decision support frameworks provide varied and extensive tools for conservation planning and management. However, using any framework in isolation risks diminishing potential benefits since no one framework covers the full spectrum of potential conservation planning and decision challenges. We describe two case studies that have effectively deployed tools from across conservation frameworks to improve conservation actions and outcomes. Attention to the critical questions for conservation project planning should allow practitioners to operate within any framework and adapt tools to suit their specific management context. We call on conservation researchers and practitioners to regularly use decision support tools as standard practice for framing both practice and research.
Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. ...However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine.
Myeloid cell populations isolated from colonic inflammatory bowel disease (IBD) or murine dextran sulphate sodium (DSS) induced colitis were assessed using flow cytometry and compared to healthy controls. In addition, mRNA expression profiles in human and murine colon samples, and in macrophages and monocytes from healthy and inflamed murine colons, were analysed by quantitative PCR (qPCR) and mRNA microarray.
We show that the monocyte:macrophage balance is disrupted in colon inflammation to favour recruitment of CD14
HLA-DR
cells in humans, and Ly6C
monocytes in mice. In addition, we identify that murine blood monocytes receive systemic signals enabling increased release of IL-1β prior to egress from the blood into the colon. Further, once within the colon and relative to other myeloid cells, monocytes represent the dominant local source of both IL-1β and TNF. Finally, our data reveal that, independent of inflammation, murine colon macrophages act as a major source of
and
chemokines that trigger further recruitment of their pro-inflammatory monocyte precursors.
Our work suggests that strategies targeting macrophage-mediated monocyte recruitment may represent a promising approach for limiting the chronic inflammation that characterises IBD.
Infection by soil transmitted parasitic helminths, such as Trichuris spp, are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections are poorly understood. ...Here we show that p43, the single most abundant protein in T. muris excretions/secretions, is non-immunogenic during infection and has an unusual sequence and structure containing subdomain homology to thrombospondin type 1 and interleukin (IL)-13 receptor (R) α2. Binding of p43 to IL-13, the key effector cytokine responsible for T. muris expulsion, inhibits IL-13 function both in vitro and in vivo. Tethering of p43 to matrix proteoglycans presents a bound source of p43 to facilitate interaction with IL-13, which may underpin chronic intestinal infection. Our results suggest that exploiting the biology of p43 may open up new approaches to modulating IL-13 function and control of Trichuris infections.
Data transport across short electrical wires is limited by both bandwidth and power density, which creates a performance bottleneck for semiconductor microchips in modern computer systems--from ...mobile phones to large-scale data centres. These limitations can be overcome by using optical communications based on chip-scale electronic-photonic systems enabled by silicon-based nanophotonic devices. However, combining electronics and photonics on the same chip has proved challenging, owing to microchip manufacturing conflicts between electronics and photonics. Consequently, current electronic-photonic chips are limited to niche manufacturing processes and include only a few optical devices alongside simple circuits. Here we report an electronic-photonic system on a single chip integrating over 70 million transistors and 850 photonic components that work together to provide logic, memory, and interconnect functions. This system is a realization of a microprocessor that uses on-chip photonic devices to directly communicate with other chips using light. To integrate electronics and photonics at the scale of a microprocessor chip, we adopt a 'zero-change' approach to the integration of photonics. Instead of developing a custom process to enable the fabrication of photonics, which would complicate or eliminate the possibility of integration with state-of-the-art transistors at large scale and at high yield, we design optical devices using a standard microelectronics foundry process that is used for modern microprocessors. This demonstration could represent the beginning of an era of chip-scale electronic-photonic systems with the potential to transform computing system architectures, enabling more powerful computers, from network infrastructure to data centres and supercomputers.
This guideline addressed VTE prevention in hospitalized medical patients, outpatients with cancer, the chronically immobilized, long-distance travelers, and those with asymptomatic thrombophilia.
...This guideline follows methods described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.
For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C). For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C). In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B).
Decisions regarding prophylaxis in nonsurgical patients should be made after consideration of risk factors for both thrombosis and bleeding, clinical context, and patients' values and preferences.
•Cannabis use is rising more rapidly among individuals with serious mental illness.•In this population, use is associated with more psychiatric hospitalizations.•Regulators should carefully ...scrutinize health claims in emerging cannabis markets.
Cannabis use is on the rise, but it is unclear how use is changing among individuals with serious psychological distress (SPD) compared to the general population as well as what associations this may have with mental health service use.
Retrospective cohort study using the National Survey on Drug Use and Health (NSDUH) 2009–19 public use files of 447,228 adults aged ≥ 18 years. Multivariable logistic regression and predictive margin methods were used to estimate linear time trends in any and greater-than-weekly levels of cannabis use by year and SPD status and rates of psychiatric hospitalization and outpatient mental health care.
Findings: Rates of any and weekly-plus cannabis use increased similarly among individuals with SPD compared to those without from 200 to 2014 but more rapidly in SPD every year from 2015 to 2019 (p < 0.001). Among individuals with SPD, no use was associated with a 4.2 % probability of psychiatric hospitalization, significantly less than less-than-weekly (5.0 %, p = 0.037) and weekly-plus cannabis use (5.1 %, p = 0.028). For outpatient mental health care, no use was associated with a 27.4 % probability (95 % CI 26.7–28.1 %) of any outpatient care, significantly less than less than weekly use (32.6 % probability, p < 0.001) and weekly-plus use (29.9 % probability, p = 0.01).
Cannabis use is increasing more rapidly among individuals with SPD than the general population, and is associated with increased rates of psychiatric hospitalization and outpatient service use. These findings can inform policy makers looking to tailor regulations on advertising for cannabis and develop public health messaging on cannabis use by people with mental illness.
Smartphone Spectrometers McGonigle, Andrew J S; Wilkes, Thomas C; Pering, Tom D ...
Sensors,
01/2018, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Smartphones are playing an increasing role in the sciences, owing to the ubiquitous proliferation of these devices, their relatively low cost, increasing processing power and their suitability for ...integrated data acquisition and processing in a 'lab in a phone' capacity. There is furthermore the potential to deploy these units as nodes within Internet of Things architectures, enabling massive networked data capture. Hitherto, considerable attention has been focused on imaging applications of these devices. However, within just the last few years, another possibility has emerged: to use smartphones as a means of capturing spectra, mostly by coupling various classes of fore-optics to these units with data capture achieved using the smartphone camera. These highly novel approaches have the potential to become widely adopted across a broad range of scientific e.g., biomedical, chemical and agricultural application areas. In this review, we detail the exciting recent development of smartphone spectrometer hardware, in addition to covering applications to which these units have been deployed, hitherto. The paper also points forward to the potentially highly influential impacts that such units could have on the sciences in the coming decades.
GISS‐E2.1: Configurations and Climatology Kelley, Maxwell; Schmidt, Gavin A; Nazarenko, Larissa ...
Journal of advances in modeling earth systems,
August 2020, Letnik:
12, Številka:
8
Journal Article
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This paper describes the GISS‐E2.1 contribution to the Coupled Model Intercomparison Project, Phase 6 (CMIP6). This model version differs from the predecessor model (GISS‐E2) chiefly due to ...parameterization improvements to the atmospheric and ocean model components, while keeping atmospheric resolution the same. Model skill when compared to modern era climatologies is significantly higher than in previous versions. Additionally, updates in forcings have a material impact on the results. In particular, there have been specific improvements in representations of modes of variability (such as the Madden‐Julian Oscillation and other modes in the Pacific) and significant improvements in the simulation of the climate of the Southern Oceans, including sea ice. The effective climate sensitivity to 2xCO2 is slightly higher than previously at 2.7‐‐3.1°C (depending on version), and is a result of lower CO2 radiative forcing and stronger positive feedbacks.
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