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Nicotinic acid has, like the Roman God Janus, two faces. One is the vitamin. The other is the broad‐spectrum lipid drug. The Canadian pathologist Rudolf Altschul discovered 50 years ago that ...nicotinic acid in gram doses lowered plasma levels of cholesterol. From the point of view of treatment of the dyslipidaemias that are risk factors for clinical atherosclerosis nicotinic acid is a miracle drug. It lowers the levels of all atherogenic lipoproteins – VLDL and LDL with subclasses as well as Lp(a) – and in addition it raises more than any other drug the levels of the protective HDL lipoproteins. Trials have shown that treatment with nicotinic acid reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The new combination treatment with statin‐lowering LDL and nicotinic acid‐raising HDL is reviewed. A basic effect of nicotinic acid is the inhibition of fat‐mobilizing lipolysis in adipose tissue leading to a lowering of plasma free fatty acids, which has many metabolic implications which are reviewed. The very recent discovery of a nicotinic acid receptor and the finding that the drug stimulates the expression of the ABCA 1 membrane cholesterol transporter have paved the way for exciting and promising new 50 years in the history of nicotinic acid.
Multivariate pattern analysis (MVPA) or brain decoding methods have become standard practice in analyzing fMRI data. Although decoding methods have been extensively applied in brain–computer ...interfaces, these methods have only recently been applied to time series neuroimaging data such as MEG and EEG to address experimental questions in cognitive neuroscience. In a tutorial style review, we describe a broad set of options to inform future time series decoding studies from a cognitive neuroscience perspective. Using example MEG data, we illustrate the effects that different options in the decoding analysis pipeline can have on experimental results where the aim is to “decode” different perceptual stimuli or cognitive states over time from dynamic brain activation patterns. We show that decisions made at both preprocessing (e.g., dimensionality reduction, subsampling, trial averaging) and decoding (e.g., classifier selection, cross-validation design) stages of the analysis can significantly affect the results. In addition to standard decoding, we describe extensions to MVPA for time-varying neuroimaging data including representational similarity analysis, temporal generalization, and the interpretation of classifier weight maps. Finally, we outline important caveats in the design and interpretation of time series decoding experiments.
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this ...hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
► Tau pathology propagates to surrounding mRNA-negative cells (neurons and astrocytes) ► Human tau protein spreads misfolding to downstream synaptically connected areas ► Human tau seeds misfolding of mouse tau ► mRNA-negative DG neurons developed tangles
Alzheimer's tangles occur in anatomically connected regions. de Calignon et al. expressed tauP301L exclusively in mouse entorhinal cortex and found that with age, tangles occur both locally and in entorhinal projection targets, suggesting that tau may propagate across synapses.
The Physical Activity Guidelines for Americans Piercy, Katrina L; Troiano, Richard P; Ballard, Rachel M ...
JAMA : the journal of the American Medical Association,
11/2018, Letnik:
320, Številka:
19
Journal Article
Recenzirano
Odprti dostop
Approximately 80% of US adults and adolescents are insufficiently active. Physical activity fosters normal growth and development and can make people feel, function, and sleep better and reduce risk ...of many chronic diseases.
To summarize key guidelines in the Physical Activity Guidelines for Americans, 2nd edition (PAG).
The 2018 Physical Activity Guidelines Advisory Committee conducted a systematic review of the science supporting physical activity and health. The committee addressed 38 questions and 104 subquestions and graded the evidence based on consistency and quality of the research. Evidence graded as strong or moderate was the basis of the key guidelines. The Department of Health and Human Services (HHS) based the PAG on the 2018 Physical Activity Guidelines Advisory Committee Scientific Report.
The PAG provides information and guidance on the types and amounts of physical activity to improve a variety of health outcomes for multiple population groups. Preschool-aged children (3 through 5 years) should be physically active throughout the day to enhance growth and development. Children and adolescents aged 6 through 17 years should do 60 minutes or more of moderate-to-vigorous physical activity daily. Adults should do at least 150 minutes to 300 minutes a week of moderate-intensity, or 75 minutes to 150 minutes a week of vigorous-intensity aerobic physical activity, or an equivalent combination of moderate- and vigorous-intensity aerobic activity. They should also do muscle-strengthening activities on 2 or more days a week. Older adults should do multicomponent physical activity that includes balance training as well as aerobic and muscle-strengthening activities. Pregnant and postpartum women should do at least 150 minutes of moderate-intensity aerobic activity a week. Adults with chronic conditions or disabilities, who are able, should follow the key guidelines for adults and do both aerobic and muscle-strengthening activities. Recommendations emphasize that moving more and sitting less will benefit nearly everyone. Individuals performing the least physical activity benefit most by even modest increases in moderate-to-vigorous physical activity. Additional benefits occur with more physical activity. Both aerobic and muscle-strengthening physical activity are beneficial.
The Physical Activity Guidelines for Americans, 2nd edition, provides information and guidance on the types and amounts of physical activity that provide substantial health benefits. Health professionals and policy makers should facilitate awareness of the guidelines and promote the health benefits of physical activity and support efforts to implement programs, practices, and policies to facilitate increased physical activity and to improve the health of the US population.
Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of ...lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural aqueous environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations. MD simulations integrate protein flexibility and the complicated role of water, thereby providing a more realistic assessment of the complex kinetics and thermodynamics at play. In this review, we describe the evolution of various cosolvent-based MD techniques and highlight a myriad of potential applications for such technologies in computational drug development.
Mitochondrial permeability transition pore (mPTP) plays a central role in alterations of mitochondrial structure and function leading to neuronal injury relevant to aging and neurodegenerative ...diseases including Alzheimer's disease (AD). mPTP putatively consists of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocator (ANT) and cyclophilin D (CypD). Reactive oxygen species (ROS) increase intra-cellular calcium and enhance the formation of mPTP that leads to neuronal cell death in AD. CypD-dependent mPTP can play a crucial role in ischemia/reperfusion injury. The interaction of amyloid beta peptide (Aβ) with CypD potentiates mitochondrial and neuronal perturbation. This interaction triggers the formation of mPTP, resulting in decreased mitochondrial membrane potential, impaired mitochondrial respiration function, increased oxidative stress, release of cytochrome c, and impaired axonal mitochondrial transport. Thus, the CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of AD. Designing small molecules to block this interaction would lessen the effects of Aβ neurotoxicity. This review summarizes the recent progress on mPTP and its potential therapeutic target for neurodegenerative diseases including AD. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.
•Mitochondrial permeability transition pore (mPTP) plays a central role in the development of Alzheimer's disease (AD).•Cyclophilin D (CypD) and reactive oxygen species are also involved in neuronal cell death in AD through mPTP.•CypD-dependent mPTP is directly linked to the cellular and synaptic perturbations in AD.•mPTP as a potential therapeutic target for neurodegenerative diseases including AD.
Warming climate, melting ice, rising seas
We know that the sea level will rise as climate warms. Nevertheless, accurate projections of how much sea-level rise will occur are difficult to make based ...solely on modern observations. Determining how ice sheets and sea level have varied in past warm periods can help us better understand how sensitive ice sheets are to higher temperatures. Dutton
et al.
review recent interdisciplinary progress in understanding this issue, based on data from four different warm intervals over the past 3 million years. Their synthesis provides a clear picture of the progress we have made and the hurdles that still exist.
Science
, this issue
10.1126/science.aaa4019
Reconstructing past magnitudes, rates, and sources of sea-level rise can help project what our warmer future may hold.
BACKGROUND
Although thermal expansion of seawater and melting of mountain glaciers have dominated global mean sea level (GMSL) rise over the last century, mass loss from the Greenland and Antarctic ice sheets is expected to exceed other contributions to GMSL rise under future warming. To better constrain polar ice-sheet response to warmer temperatures, we draw on evidence from interglacial periods in the geologic record that experienced warmer polar temperatures and higher GMSLs than present. Coastal records of sea level from these previous warm periods demonstrate geographic variability because of the influence of several geophysical processes that operate across a range of magnitudes and time scales. Inferring GMSL and ice-volume changes from these reconstructions is nontrivial and generally requires the use of geophysical models.
ADVANCES
Interdisciplinary studies of geologic archives have ushered in a new era of deciphering magnitudes, rates, and sources of sea-level rise. Advances in our understanding of polar ice-sheet response to warmer climates have been made through an increase in the number and geographic distribution of sea-level reconstructions, better ice-sheet constraints, and the recognition that several geophysical processes cause spatially complex patterns in sea level. In particular, accounting for glacial isostatic processes helps to decipher spatial variability in coastal sea-level records and has reconciled a number of site-specific sea-level reconstructions for warm periods that have occurred within the past several hundred thousand years. This enables us to infer that during recent interglacial periods, small increases in global mean temperature and just a few degrees of polar warming relative to the preindustrial period resulted in ≥6 m of GMSL rise. Mantle-driven dynamic topography introduces large uncertainties on longer time scales, affecting reconstructions for time periods such as the Pliocene (~3 million years ago), when atmospheric CO
2
was ~400 parts per million (ppm), similar to that of the present. Both modeling and field evidence suggest that polar ice sheets were smaller during this time period, but because dynamic topography can cause tens of meters of vertical displacement at Earth’s surface on million-year time scales and uncertainty in model predictions of this signal are large, it is currently not possible to make a precise estimate of peak GMSL during the Pliocene.
OUTLOOK
Our present climate is warming to a level associated with significant polar ice-sheet loss in the past, but a number of challenges remain to further constrain ice-sheet sensitivity to climate change using paleo–sea level records. Improving our understanding of rates of GMSL rise due to polar ice-mass loss is perhaps the most societally relevant information the paleorecord can provide, yet robust estimates of rates of GMSL rise associated with polar ice-sheet retreat and/or collapse remain a weakness in existing sea-level reconstructions. Improving existing magnitudes, rates, and sources of GMSL rise will require a better (global) distribution of sea-level reconstructions with high temporal resolution and precise elevations and should include sites close to present and former ice sheets. Translating such sea-level data into a robust GMSL signal demands integration with geophysical models, which in turn can be tested through improved spatial and temporal sampling of coastal records.
Further development is needed to refine estimates of past sea level from geochemical proxies. In particular, paired oxygen isotope and Mg/Ca data are currently unable to provide confident, quantitative estimates of peak sea level during these past warm periods. In some GMSL reconstructions, polar ice-sheet retreat is inferred from the total GMSL budget, but identifying the specific ice-sheet sources is currently hindered by limited field evidence at high latitudes. Given the paucity of such data, emerging geochemical and geophysical techniques show promise for identifying the sectors of the ice sheets that were most vulnerable to collapse in the past and perhaps will be again in the future.
Peak global mean temperature, atmospheric CO
2
, maximum global mean sea level (GMSL), and source(s) of meltwater.
Light blue shading indicates uncertainty of GMSL maximum. Red pie charts over Greenland and Antarctica denote fraction (not location) of ice retreat.
Interdisciplinary studies of geologic archives have ushered in a new era of deciphering magnitudes, rates, and sources of sea-level rise from polar ice-sheet loss during past warm periods. Accounting for glacial isostatic processes helps to reconcile spatial variability in peak sea level during marine isotope stages 5e and 11, when the global mean reached 6 to 9 meters and 6 to 13 meters higher than present, respectively. Dynamic topography introduces large uncertainties on longer time scales, precluding robust sea-level estimates for intervals such as the Pliocene. Present climate is warming to a level associated with significant polar ice-sheet loss in the past. Here, we outline advances and challenges involved in constraining ice-sheet sensitivity to climate change with use of paleo–sea level records.
•Hybrid MABR process makes understanding the metabolism of purely anoxic suspended growth more important.•Only 60 % of particulate and colloidal organic matter metabolized under anoxic versus aerobic ...conditions.•Fully anoxic suspended growth treatment benefits MABR technology by providing sCOD removal and pCOD/cCOD capture.•Bio-P removal under strict anaerobic/anoxic conditions significantly reduced compared to anaerobic/aerobic conditions.•Reduced anoxic bio-P due to less hydrolysis and fermentation and reduced carbon processing efficiency of denitrifying PAOs.
Fully anoxic suspended growth treatment of domestic wastewater is rarely performed in practice at large scale. However, recent advances in membrane aerated biofilm reactor (MABR) technology can enable the “hybrid” concept that couples nitrification in the MABR with anoxic suspended growth for biological nitrogen removal. Small scale sequencing batch reactors were constructed to compare high-rate anoxic metabolization of influent carbon and biological phosphorus removal side-by-side with a conventional aerated system in a low-strength domestic wastewater (COD/TN ratio of approximately 6). Little differences existed in the oxidation of soluble readily biodegradable organic material between the two systems, but hydrolysis of particulate and colloidal organic matter in the anoxic reactor over a range of solid retention times was 60 % of the aerobic reactor. Reduced hydrolysis limited the amount of carbon available to ferment to volatile fatty acid (VFA), adversely impacting anoxic biological phosphorus removal (bio-P) process rates, and ortho-P removal performance was diminished by more than half at equivalent SRTs. At optimal growth conditions, i.e., an SRT of approximately 8 days and with supplementary VFA, ortho-P removal from the influent averaged roughly 75 %. Experimentation with supplemented acetic acid showed reduced anoxic metabolic efficiency, quantified via a P/O ratio of 0.90 versus 1.7 for the aerobic system, although overall anoxic bio-P removal demonstrably increased with external carbon.
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Growing consensus suggests that frailty-associated risks should inform shared surgical decision making. However, it is not clear how best to screen for frailty in preoperative surgical populations.
...To develop and validate the Risk Analysis Index (RAI), a 14-item instrument used to measure surgical frailty. It can be calculated prospectively (RAI-C), using a clinical questionnaire, or retrospectively (RAI-A), using variables from the surgical quality improvement databases (Veterans Affairs or American College of Surgeons National Surgical Quality Improvement Projects).
Single-site, prospective cohort from July 2011 to September 2015 at the Veterans Affairs Nebraska-Western Iowa Heath Care System, a Level 1b Veterans Affairs Medical Center. The study included all patients presenting to the medical center for elective surgery.
We assessed the RAI-C for all patients scheduled for surgery, linking these scores to administrative and quality improvement data to calculate the RAI-A and the modified Frailty Index.
Receiver operator characteristics and C statistics for each measure predicting postoperative mortality and morbidity.
Of the participants, the mean (SD) age was 60.7 (13.9) years and 249 participants (3.6%) were women. We assessed the RAI-C 10 698 times, from which we linked 6856 unique patients to mortality data. The C statistic predicting 180-day mortality for the RAI-C was 0.772. Of these 6856 unique patients, we linked 2785 to local Veterans Affairs Surgeons National Surgical Quality Improvement Projects data and calculated the C statistic for both the RAI-A (0.823) and RAI-C (0.824), along with the correlation between the 2 scores (r = 0.478; P < .001). Of these 2785 patients, there were sufficient data to calculate the modified Frailty Index for 1021, in which the C statistics were 0.865 (RAI-A), 0.797 (RAI-C), and 0.811 (modified Frailty Index). The correlation between the RAI-A and RAI-C was 0.547, and the correlations of the modified Frailty Index to the RAI-A and RAI-C were 0.301 and 0.269, respectively (all P < .001). A cutoff of RAI-C of at least 21 classified 18.3% patients as "frail" with a sensitivity of 0.50 and specificity of 0.82, whereas the RAI-A was less sensitive (0.25) and more specific (0.97), classifying only 3.7% as "frail."
The RAI-C and RAI-A represent effective tools for measuring frailty in surgical populations with predictive ability on par with other frailty tools. Moderate correlation between the measures suggests convergent validity. The RAI-C offers the advantage of prospective, preoperative assessment that is proved feasible for large-scale screening in clinical practice. However, further efforts should be directed at determining the optimal components of preoperative frailty assessment.
Developing probes for the detection of reactive oxygen species (ROS), a hallmark of many pathophysiological process, is imperative to both understanding the precise roles of ROS in many ...life-threatening diseases and optimizing therapeutic interventions. We herein report an all-in-one fluorescent semiconducting polymer based far-red to near-infrared (NIR) Pdot nanoprobe for the ratiometric detection of hypochlorous acid (HOCl). The fabrication takes the advantage of flexible polymer design by incorporating target-sensitive and target-inert fluorophores into a single conjugated polymer to avoid leakage or differential photobleaching problems existed in other nanoprobes. The obtained nanoprobe has improved performance in HOCl sensing, such as high brightness, ideal far-red to NIR optical window, excellent photostability, self-referenced ratiometric response, fast response, and high selectivity. The dual-emission property allows the sensitive imaging of HOCl fluctuations produced in living macrophage cells and peritonitis of living mice with high contrast. This study not only provides a powerful and promising nanoprobe to be potentially used in the investigations of in situ HOCl status of diseases in living systems but also puts forward the design strategy of a new category of ratiometric fluorescent probes facilitating precise and reliable measurement in biological systems.
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