Mammalian phospholipase C Kadamur, Ganesh; Ross, Elliott M
Annual review of physiology,
01/2013, Letnik:
75
Journal Article
Recenzirano
Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP(2)) to inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol (DAG). DAG and IP(3) each control diverse cellular processes ...and are also substrates for synthesis of other important signaling molecules. PLC is thus central to many important interlocking regulatory networks. Mammals express six families of PLCs, each with both unique and overlapping controls over expression and subcellular distribution. Each PLC also responds acutely to its own spectrum of activators that includes heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca(2+), and phospholipids. Mammalian PLCs are autoinhibited by a region in the catalytic TIM barrel domain that is the target of much of their acute regulation. In combination, the PLCs act as a signaling nexus that integrates numerous signaling inputs, critically governs PIP(2) levels, and regulates production of important second messengers to determine cell behavior over the millisecond to hour timescale.
Several degradative systems assist in formation of multinucleated terminally differentiated myotubes. However, the role of autophagy in this process has not been examined. GFP-LC3B (light chain 3 ...beta) puncta, LC3B-II protein and LysoTracker fluorescence increased during C2C12 cell differentiation. Importantly, accumulation of LC3B-II protein occurred in CQ (chloroquine)-treated cells throughout differentiation. Furthermore, BECN1 (beclin 1), ATG7 (autophagy-related 7) and ATG12-5 protein increased, whereas SQSTM1/p62 (sequestosome 1) protein was rapidly reduced during differentiation. A transient decrease in BECN1-BCL2 association was observed from day 0.5 to 2 of differentiation. Chemical inhibition of JNK (c-Jun N-terminal kinase) during differentiation reduced LC3B-II protein and GFP-LC3B puncta and maintained BECN1-BCL2 association. Inhibition of autophagy by 3MA (3-methyladenine) or shRNA against Atg7 (shAtg7) resulted in lower myosin heavy chain expression, as well as impaired myoblast fusion and differentiation. Interestingly, 3MA treatment during differentiation increased transient CASP3 (caspase 3) activation, DNA fragmentation and the percentage of apoptotic nuclei. Similarly, shAtg7 cells had increased DNA fragmentation during differentiation compared with the controls. Collectively, these data demonstrate that autophagy increases and is required during myoblast differentiation. Moreover, autophagy protects differentiating myoblasts from apoptotic cell death.
Managing Stable Ischemic Heart Disease Antman, Elliott M; Braunwald, Eugene
The New England journal of medicine,
04/2020, Letnik:
382, Številka:
15
Journal Article
Precision medicine in cardiology Antman, Elliott M; Loscalzo, Joseph
Nature reviews cardiology,
10/2016, Letnik:
13, Številka:
10
Journal Article
Recenzirano
The cardiovascular research and clinical communities are ideally positioned to address the epidemic of noncommunicable causes of death, as well as advance our understanding of human health and ...disease, through the development and implementation of precision medicine. New tools will be needed for describing the cardiovascular health status of individuals and populations, including 'omic' data, exposome and social determinants of health, the microbiome, behaviours and motivations, patient-generated data, and the array of data in electronic medical records. Cardiovascular specialists can build on their experience and use precision medicine to facilitate discovery science and improve the efficiency of clinical research, with the goal of providing more precise information to improve the health of individuals and populations. Overcoming the barriers to implementing precision medicine will require addressing a range of technical and sociopolitical issues. Health care under precision medicine will become a more integrated, dynamic system, in which patients are no longer a passive entity on whom measurements are made, but instead are central stakeholders who contribute data and participate actively in shared decision-making. Many traditionally defined diseases have common mechanisms; therefore, elimination of a siloed approach to medicine will ultimately pave the path to the creation of a universal precision medicine environment.
As a non-beam-based additive manufacturing (AM) method, binder jet 3D printing (BJ3DP) is a process in which a liquid binder is jetted on layers of powdered materials, selectively joined, and then ...followed by densification process. Among AM technologies, binder jetting holds distinctive promise because of the possibility of rapid production of complex structures to achieve isotropic properties in the 3D printed samples. By taking advantage of traditional powder metallurgy, BJ3DP machines can produce prototypes in which material properties and surface finish are similar to those attained with traditional powder metallurgy. Various powdered materials have been 3D printed, but a typical challenge during BJ3DP is developing printing and post-processing methods that maximize part performance. Therefore, a detailed review of the physical processes during 3D printing and the fundamental science of densification after sintering and post–heat treatment steps are provided to understand the microstructural evolution and properties of binder jetted parts. Furthermore, to determine the effects of the binder jetting process on metallurgical properties, the role of powder characteristics (e.g., morphology, mean size, distribution), printing process parameters (e.g., layer thickness, print orientation, binder saturation, print speed, drying time), sintering (e.g., temperature, holding time), and post-processing are discussed. With the development of AM technologies and the need for post-processing in 3D printed parts, understanding the microstructural evolution during densification is necessary and here, processing steps are explained. Finally, opportunities for future advancement are addressed.
Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug ...Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively.
Human activities introduce a variety of chemicals to the Laurentian Great Lakes including pesticides, pharmaceuticals, flame retardants, plasticizers, and solvents (collectively referred to as ...contaminants of emerging concern or CECs) potentially threatening the vitality of these valuable ecosystems. We conducted a basin-wide study to identify the presence of CECs and other chemicals of interest in 12 U.S. tributaries to the Laurentian Great Lakes during 2013 and 2014. A total of 292 surface-water and 80 sediment samples were collected and analyzed for approximately 200 chemicals. A total of 32 and 28 chemicals were detected in at least 30% of water and sediment samples, respectively. Concentrations ranged from 0.0284 (indole) to 72.2 (cholesterol) μg/L in water and 1.75 (diphenhydramine) to 20,800 μg/kg (fluoranthene) in sediment. Cluster analyses revealed chemicals that frequently co-occurred such as pharmaceuticals and flame retardants at sites receiving similar inputs such as wastewater treatment plant effluent. Comparison of environmental concentrations to water and sediment-quality benchmarks revealed that polycyclic aromatic hydrocarbon concentrations often exceeded benchmarks in both water and sediment. Additionally, bis(2-ethylhexyl) phthalate and dichlorvos concentrations exceeded water-quality benchmarks in several rivers. Results from this study can be used to understand organism exposure, prioritize river basins for future management efforts, and guide detailed assessments of factors influencing transport and fate of CECs in the Great Lakes Basin.
Evolving concepts in dilated cardiomyopathy Merlo, Marco; Cannatà, Antonio; Gobbo, Marco ...
European journal of heart failure,
February 2018, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Dilated cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co‐morbidities. The ...prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red‐flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non‐pharmacological evidence‐based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations.
Quantifying contributions of local and regional NOx emission sources is an important initial step towards accurately assessing improvements in NOx emission reduction efforts. Current global NOx ...inventories report large uncertainties in contributions of some NOx sources, especially diffuse sources (e.g. lightning and soil NOx). Examining the isotopic composition of NOx and its oxidation products (NOy) is one approach to further constrain contributions from these sources. While natural and anthropogenically-derived NOx emissions are reported to have relatively distinct δ15N values that could aid NOx source apportionment studies, existing δ15N–NOx source data is limited and variable collection approaches have been employed. To build on existing δ15N–NOx source data, inexpensive and easily deployable passive samplers were used to collect nitrogen dioxide (NO2) emissions and its oxidation product, nitric acid (HNO3), from multiple emission sources including livestock waste, fertilized soils, and vehicles. The resulting isotope data provides evidence that passive samplers can be used across a range of environmental conditions with widely varying NO2 concentrations and NO2 isotopic compositions. Using this approach, we report the first δ15N and δ18O–NO2 of livestock waste emissions, as well as the first measurements of δ18O–NO2 from biogenic soil and vehicle emissions. We observe the highest δ15N–NO2 values to date of vehicle emissions and investigate potential fractionations associated with oxidation and equilibrium processes. The large differences reported here between δ15N–NO2 values from fossil fuel-based sources and microbially-produced sources allows for identification and possible quantification of source contributions to ambient NOx concentrations.
•We report the δ15N and δ18O values of natural and anthropogenic NOx emission sources.•We report the first δ15N and δ18O–NO2 values of livestock waste emissions.•We report the first δ18O–NO2 values of biogenic soil and vehicle emissions.•We provide evidence for passive sampler use to collect NOx for isotope analysis.
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