Hypertriglyceridemia (triglycerides 200–499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently ...observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2–4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non–high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.
MicroRNA (miRNA) sponges are transcripts with repeated miRNA antisense sequences that can sequester miRNAs from endogenous targets. MiRNA sponges are valuable tools for miRNA loss-of-function studies ...both in vitro and in vivo. We developed a fast and flexible method to generate miRNA sponges and tested their efficiency in various assays. Using a single directional ligation reaction we generated sponges with 10 or more miRNA binding sites. Luciferase and AGO2-immuno precipitation (IP) assays confirmed effective binding of the miRNAs to the sponges. Using a GFP competition assay we showed that miR-19 sponges with central mismatches in the miRNA binding sites are efficient miRNA inhibitors while sponges with perfect antisense binding sites are not. Quantification of miRNA sponge levels suggests that this is at least in part due to degradation of the perfect antisense sponge transcripts. Finally, we provide evidence that combined inhibition of miRNAs of the miR-17∼92 cluster results in a more effective growth inhibition as compared to inhibition of individual miRNAs. In conclusion, we describe and validate a method to rapidly generate miRNA sponges for miRNA loss-of-function studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic ...agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-) ) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
When intense lightwaves accelerate electrons through a solid, the emerging high-order harmonic (HH) radiation offers key insights into the material
. Sub-optical-cycle dynamics-such as dynamical ...Bloch oscillations
, quasiparticle collisions
, valley pseudospin switching
and heating of Dirac gases
-leave fingerprints in the HH spectra of conventional solids. Topologically non-trivial matter
with invariants that are robust against imperfections has been predicted to support unconventional HH generation
. Here we experimentally demonstrate HH generation in a three-dimensional topological insulator-bismuth telluride. The frequency of the terahertz driving field sharply discriminates between HH generation from the bulk and from the topological surface, where the unique combination of long scattering times owing to spin-momentum locking
and the quasi-relativistic dispersion enables unusually efficient HH generation. Intriguingly, all observed orders can be continuously shifted to arbitrary non-integer multiples of the driving frequency by varying the carrier-envelope phase of the driving field-in line with quantum theory. The anomalous Berry curvature warranted by the non-trivial topology enforces meandering ballistic trajectories of the Dirac fermions, causing a hallmark polarization pattern of the HH emission. Our study provides a platform to explore topology and relativistic quantum physics in strong-field control, and could lead to non-dissipative topological electronics at infrared frequencies.
Speed in Clinical Magnetic Resonance Runge, Val M; Richter, Johannes K; Heverhagen, Johannes T
Investigative radiology,
2017-January, 2017-Jan, 2017-1-00, 20170101, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACTThe relevant clinical accelerated magnetic resonance techniques that are available currently for routine patient examinations are reviewed, presenting and discussing the benefits therein when ...compared with more conventional scans. The focus is on clinical use and practicality, with the review divided into 3 sections. Improvements in 3-dimensional acquisition are first discussed, specifically controlled aliasing in parallel imaging results in higher acceleration, related radial techniques, and CAIPI-Dixon-TWIST-VIBE. Simultaneous multislice imaging is then reviewed, focusing on current implementation for 2-dimensional imaging, including both echo-planar and fast spin echo techniques. The final topic is that of sparse reconstruction (data sparsity), discussing the principles therein, challenges, and current applications. Guidance in terms of clinical use for accelerated techniques is provided, focusing on enabling faster and improved clinical scan results.
The spin-orbit interaction plays a crucial role in diverse fields of condensed matter, including the investigation of Majorana fermions, topological insulators, quantum information and spintronics. ...In III-V zinc-blende semiconductor heterostructures, two types of spin-orbit interaction--Rashba and Dresselhaus--act on the electron spin as effective magnetic fields with different directions. They are characterized by coefficients α and β, respectively. When α is equal to β, the so-called persistent spin helix symmetry is realized. In this condition, invariance with respect to spin rotations is achieved even in the presence of the spin-orbit interaction, implying strongly enhanced spin lifetimes for spatially periodic spin modes. Existing methods to evaluate α/β require fitting analyses that often include ambiguity in the parameters used. Here, we experimentally demonstrate a simple and fitting parameter-free technique to determine α/β and to deduce the absolute values of α and β. The method is based on the detection of the effective magnetic field direction and the strength induced by the two spin-orbit interactions. Moreover, we observe the persistent spin helix symmetry by gate tuning.
High-speed infrared thermography was applied for boundary-layer transition measurements on the upper side of helicopter rotors. The transition detection is based on the analysis of a single ...instantaneous thermal image of the rotating blade and allows the determination of both the locations of the onset and of the end of the transition region. Measurements were performed on a Mach-scaled BO105 model rotor for different rotation frequencies. The transition characteristics are presented and compared to two-dimensional numerical simulations, and the measurement scatter is discussed. Additional transition measurements were performed on the main rotors of the DLR research helicopters Eurocopter BO105 and EC135. The transition behavior of the EC135 rotor blade is presented for different cases, and the effect of the contamination of the rotor blade leading edge on the laminar flow is discussed.
Summary
Members of the marine actinomycete genus Salinispora constitutively produce a characteristic orange pigment during vegetative growth. Contrary to the understanding of widespread carotenoid ...biosynthesis pathways in bacteria, Salinispora carotenoid biosynthesis genes are not confined to a single cluster. Instead, bioinformatic and genetic investigations confirm that four regions of the Salinispora tropica CNB‐440 genome, consisting of two gene clusters and two independent genes, contribute to the in vivo production of a single carotenoid. This compound, namely (2′S)‐1′‐(β‐D‐glucopyranosyloxy)‐3′,4′‐didehydro‐1′,2′‐dihydro‐φ,ψ‐caroten‐2′‐ol, is novel and has been given the trivial name ‘sioxanthin’. Sioxanthin is a C40‐carotenoid, glycosylated on one end of the molecule and containing an aryl moiety on the opposite end. Glycosylation is unusual among actinomycete carotenoids, and sioxanthin joins a rare group of carotenoids with polar and non‐polar head groups. Gene sequence homology predicts that the sioxanthin biosynthetic pathway is present in all of the Salinispora as well as other members of the family Micromonosporaceae. Additionally, this study's investigations of clustering of carotenoid biosynthetic genes in heterotrophic bacteria show that a non‐clustered genome arrangement is more common than previously suggested, with nearly half of the investigated genomes showing a non‐clustered architecture.
•Amorphous glass-coated microwires contain a tilted domain wall.•The domain wall inclination can be controlled by thermal annealing.•Surface domain wall pinning leads to strong distortion of a domain ...wall.
Domain wall dynamics in highly magnetostrictive microwires is remarkably sensitive to thermal treatment. One of the reasons is a partial release of the internal stresses that originate during the production process. Another reason is an interaction of the domain wall with local pinning sites, such as surface inhomogeneities, free volumes, or clusters of ferromagnetic atoms, present in as-cast microwires. However, the observation of domain wall shape variations after thermal treatment or following an interaction with a pinning site is challenging. In this paper, we utilize the magneto-optical Kerr effect (MOKE) to locally map the domain wall shape and velocity in cylindrical microwires. The domain wall is trapped in a magnetic potential well, moving back and forth with limited speed. Two complementary techniques are employed in the study: a laser-based setup and time-resolved MOKE microscopy. Different kinds of domain wall propagation are observed. While a planar domain wall propagates synchronously with the potential well, surface pinning gives rise to local jumps and distortions of the domain wall. We relate the first kind of motion to the pinning-free propagation of the domain wall and the second to the propagation of a distorted wall. Finally, local speed and the shapes of the domain wall before and after the introduction of an artificial pinning site are compared.
The use of genome sequences has become routine in guiding the discovery and identification of microbial natural products and their biosynthetic pathways. In silico prediction of molecular features, ...such as metabolic building blocks, physico‐chemical properties or biological functions, from orphan gene clusters has opened up the characterization of many new chemo‐ and genotypes in genome mining approaches. Here, we guided our genome mining of two predicted enediyne pathways in Salinispora tropica CNB‐440 by a DNA interference bioassay to isolate DNA‐targeting enediyne polyketides. An organic extract of S. tropica showed DNA‐interference activity that surprisingly was not abolished in genetic mutants of the targeted enediyne pathways, ST_pks1 and spo. Instead we showed that the product of the orphan type II polyketide synthase pathway, ST_pks2, is solely responsible for the DNA‐interfering activity of the parent strain. Subsequent comparative metabolic profiling revealed the lomaiviticins, glycosylated diazofluorene polyketides, as the ST_pks2 products. This study marks the first report of the 59 open reading frame lomaiviticin gene cluster (lom) and supports the biochemical logic of their dimeric construction through a pathway related to the kinamycin monomer.
Lomaiviticin gene cluster: Bioactivity‐guided genome mining links DNA‐interference activity of Salinispora tropica extracts not to anticipated enediyne gene clusters but to a type II polyketide gene cluster. This gene cluster (lom) is responsible for lomaiviticin biosynthesis.
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