Hormones can transmit signals through adenosine 3ʹ,5ʹ-monophosphate (cAMP) to precise intracellular locations. The fidelity of these responses relies on the activation of localized protein kinase A ...(PKA) holoenzymes. Association of PKA regulatory type II (RII) subunits with A-kinase–anchoring proteins (AKAPs) confers location, and catalytic (C) subunits phosphorylate substrates. Single-particle electron microscopy demonstrated that AKAP79 constrains RII-C subassemblies within 150 to 250 angstroms of its targets. Native mass spectrometry established that these macromolecular assemblies incorporated stoichiometric amounts of cAMP. Chemical-biology– and live cell–imaging techniques revealed that catalytically active PKA holoenzymes remained intact within the cytoplasm. These findings indicate that the parameters of anchored PKA holoenzyme action are much more restricted than originally anticipated.
This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, ...synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.
New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior ...safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear.
We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520.
We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78–0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71–0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78–1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88–1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50–0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50–0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year.
The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year.
Bern University Hospital.
Abstract Numerous experimental studies have attempted to determine the optimal properties for a scaffold for use in bone tissue engineering but, as yet, no computational or theoretical approach has ...been developed that suggests how best to combine the various design parameters, e.g. scaffold porosity, Young's modulus, and dissolution rate. Previous research has shown that bone regeneration during fracture healing and osteochondral defect repair can be simulated using mechanoregulation algorithms based on computing strain and/or fluid flow in the regenerating tissue. In this paper a fully three-dimensional approach is used for computer simulation of tissue differentiation and bone regeneration in a regular scaffold as a function of porosity, Young's modulus, and dissolution rate—and this is done under both low and high loading conditions. The mechanoregulation algorithm employed determines tissue differentiation both in terms of the prevailing biophysical stimulus and number of precursor cells, where cell number is computed based on a three-dimensional random-walk approach. The simulations predict that all three design variables have a critical effect on the amount of bone regenerated, but not in an intuitive way: in a low load environment, a higher porosity and higher stiffness but a medium dissolution rate gives the greatest amount of bone whereas in a high load environment the dissolution rate should be lower otherwise the scaffold will collapse—at lower initial porosities however, higher dissolution rates can be sustained. Besides showing that scaffolds may be optimised to suit the site-specific loading requirements, the results open up a new approach for computational simulations in tissue engineering.
Gold nanoparticles (AuNP) have potential as both diagnostic and therapeutic vehicles. However, selective targeting and uptake in cancer cells remains challenging. Cold atmospheric plasma (CAP) can be ...combined with AuNP to achieve synergistic anti-cancer cytotoxicity. To explore synergistic mechanisms, we demonstrate both rate of AuNP uptake and total amount accumulated in U373MG Glioblastoma multiforme (GBM) cells are significantly increased when exposed to 75 kV CAP generated by dielectric barrier discharge. No significant changes in the physical parameters of AuNP were caused by CAP but active transport mechanisms were stimulated in cells. Unlike many other biological effects of CAP, long-lived reactive species were not involved, and plasma-activated liquids did not replicate the effect. Chemical effects induced by direct and indirect exposure to CAP appears the dominant mediator of enhanced uptake. Transient physical alterations of membrane integrity played a minor role. 3D-reconstruction of deconvoluted confocal images confirmed AuNP accumulation in lysosomes and other acidic vesicles, which will be useful for future drug delivery and diagnostic strategies. Toxicity of AuNP significantly increased by 25-fold when combined with CAP. Our data indicate that direct exposure to CAP activates AuNP-dependent cytotoxicity by increasing AuNP endocytosis and trafficking to lysosomes in U373MG cells.
A successful nasal reconstruction relies heavily on a stable internal lining. Larger defects pose unique challenges for internal lining reconstruction as obtaining tissue of adequate size while ...maintaining airway patency is difficult. The prelamination technique uses a staged skin graft to the paramedian forehead flap prior to transfer. As such, a composite flap can be later transferred to reconstruct internal and external nasal defects concomitantly. This article reviews the current background, techniques, and clinical considerations in the use of the prelaminated forehead flap for nasal lining reconstruction in partial to total nasal defects.
The Biogeography of Marine Invertebrate Life Histories Marshall, Dustin J; Krug, Patrick J; Kupriyanova, Elena K ...
Annual review of ecology, evolution, and systematics,
01/2012, Letnik:
43, Številka:
1
Journal Article
Recenzirano
Biologists have long sought to identify and explain patterns in the diverse array of marine life histories. The most famous speculation about such patterns is Gunnar Thorson's suggestion that species ...producing planktonic larvae are rarer at higher latitudes (Thorson's rule). Although some elements of Thorson's rule have proven incorrect, other elements remain untested. With a wealth of new life-history data, statistical approaches, and remote-sensing technology, new insights into marine reproduction can be generated. We gathered life-history data for more than 1,000 marine invertebrates and examined patterns in the prevalence of different life histories. Systematic patterns in marine life histories exist at a range of scales, some of which support Thorson, whereas others suggest previously unrecognized relationships between the marine environment and the life histories of marine invertebrates. Overall, marine life histories covary strongly with temperature and local ocean productivity, and different regions should be managed accordingly.
The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess ...fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.
► Cardiac fumarase deletion (cFH1-KO) results in mice with elevated cardiac fumarate ► cFH1-KO is compensated for by amino acid influx into the citric acid cycle ► Nrf2 and its target genes are activated in the hearts of cFH1-KO mice ► Fumarate-related Nrf2 activation is cytoprotective and may be of therapeutic use
Facial nerve function is essential for a multitude of processes in the face, including facial movement; expression; and functions, such as eating, smiling, and blinking. When facial nerve function is ...disrupted, facial paralysis may occur and various complications for the patient may result. Much research has been conducted on the physical diagnosis, management, and treatment of facial paralysis. However, there is a lack of knowledge of the psychological and social effects of the condition. Patients may be at an increased risk for anxiety and depression, as well as negative self and social perceptions. This review analyzes the current literature on the various adverse psychological and psychosocial effects of facial paralysis, factors that may play a role, and treatment options that may help improve patients’ quality of life.
Objectives To characterize the effect of facial reanimation using masseteric nerve transfer on the masseter muscle itself, examining whether there is any demonstrable atrophy postoperatively. Methods ...Electronic medical records of adult patients who underwent facial reanimation using masseteric nerve transfer at our institution over a 15‐year period were reviewed. To account for the impact of postoperative radiation, randomly selected patients who underwent radical parotidectomy without nerve transfer and received postoperative radiation served as controls in a 1:1 fashion against those who underwent masseteric nerve transfer with postoperative radiation. Results Twenty patients were identified who underwent masseteric nerve transfer and had sufficient pre‐ and postoperative imaging to assess masseter volume (mean age 58.2, 60% female). Of the four patients who did not receive postoperative radiation, each demonstrated masseteric atrophy on the side of their nerve transfer, with a mean reduction in masseter volume of 20.6%. The remaining 16 patients were included in the case–control analysis accounting for radiation. When compared with controls, those in the study group were found to have a statistically significant difference in atrophy ( p = 0.0047) and total volume loss ( p = 0.0002). The overall reduction in masseter volume in the study group was significantly higher compared with the control group, at 41.7% and 16.6%, respectively ( p = 0.0001). Conclusion Facial reanimation utilizing masseteric nerve transfer appears to result in atrophy of the denervated masseter when compared with the contralateral muscle. This volume deficit may lead to further facial asymmetry for patients undergoing comprehensive reanimation surgery. Level of Evidence 3 Laryngoscope , 2024
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