2,950 research outputs found
Nanoparticle clearance from the airways : development and testing of a new in vitro model to investigate mucociliary clearance of aerosol particles
The current challenge in pulmonary drug delivery is to overcome and to control drug clearance from the lung. Here, the interaction with the mucociliary lung clearance plays a key role for any drug formulation technology. By today many open questions on mucociliary clearance (MC) have to be answered but suffer from limited experimental options. Considering these facts, the central part of this work was to develop a new in vitro test model to investigate the complex mechanism of MC more detailed. In a next step the new model was employed to study the influence of different factors on mucociliary particle clearance. From the overall results it can be concluded that:
1) A new embryonic chicken trachea-based in vitro model to study MC was successfully developed and characterized.
2) The model exhibits a stability and sensitivity for environmental as well as chemical influences reflecting the in vivo situation.
3) Size and ζ-potential (ZP) seem to be minor critical factors for mucociliary particle clearance, which could be shown for different polymeric particles covering a broad size and ZP range.
4) The chemical surface structure of nanoparticles was found to be a most relevant factor for MC, offering promising possibilities to achieve faster or slower particle transport.
In summary, this model may help to clarify open questions on lung clearance, strongly limiting the benefit of pulmonary drug delivery, and to realize the \u273R\u27; concept in animal testing: Reduce, Refine, and Replace.Die kontrollierte Arzneistoffelimination aus der Lunge stellt fĂŒr die Inhalative Therapie eine groĂe Herausforderung dar. Von zentraler Bedeutung, doch bis heute mit vielen offenen Fragen verbunden, ist hierbei die mukoziliĂ€re Clearance (MC). Ziel dieser Arbeit war daher die Entwicklung eines neuen in vitro Modells fĂŒr die gezielte Untersuchung mukoziliĂ€rer Transportprozesse sowie die anschlieĂende Testung verschiedener Einflussfaktoren auf die MC von Partikeln. Aufgrund der Ergebnisse dieser Arbeit können folgende SchlĂŒsse gezogen werden:
1) Ein auf embryonaler HĂŒhnertrachea basierendes in vitro Testsystem zur Untersuchung der MC wurde erfolgreich entwickelt und charakterisiert.
2) Das Modell weist gegenĂŒber Ă€uĂeren EinflĂŒssen und Arzneistoffen eine mit der in vivo Situation vergleichbare StabilitĂ€t sowie SensitivitĂ€t auf.
3) PartikelgröĂe sowie ζ-Potenzial scheinen fĂŒr die MC von untergeordneter Bedeutung zu sein, was fĂŒr verschiedene Polymerpartikel unterschiedlicher Ladung und GröĂe gezeigt werden konnte.
4) Die chemische Struktur und OberflĂ€chenbeschaffenheit nanoskaliger Partikel scheint ein wichtiger Parameter fĂŒr die MC zu sein und stellt damit einen Erfolg versprechenden Ansatz fĂŒr die kontrollierte Arzneistoffelimination aus der Lunge dar.
Zusammenfassend besteht mit diesem neuen in vitro Modell kĂŒnftig die Option, mukoziliĂ€re Transportprozesse unter Beachtung des 3R-Konzepts fĂŒr Tierexperimente (Reduce, Refine, and Replace) gezielt zu untersuchen und aufzuklĂ€ren
Towards understanding crossover for Cartesian Genetic Programming
Unlike in traditional Genetic Programming, Cartesian Genetic Programming (CGP) does not commonly feature a recombination/crossover operator, although recombination plays an important role in other evolutionary techniques, including Genetic Programming from which CGP originates. Instead, CGP mainly depends on mutation and selection operators in their evolutionary search. To this day, it is still unclear as to why CGPâs performance does not generally improve with the addition of crossover. In this work, we argue that CGPâs positional bias might be a reason for this phenomenon. This bias describes a skewed distribution of active and inactive nodes, which might lead to destructive behaviour of standard recombination operators. We provide a first assessment with preliminary results. No final conclusion to this hypothesis can be drawn yet, as more thorough evaluations must be done first. However, our first results show promising trends and may lay the foundationf or future work
3.5ââkW coherently combined ultrafast fiber laser
An ultrafast laser based on the coherent beam combination of four ytterbium-doped step-index fiber amplifiers is presented. The system delivers an average power of 3.5 kW and a pulse duration of 430 fs at an 80 MHz repetition rate. The beam quality is excellent (M2<1.24·1.10), and the relative intensity noise is as low as 1% in the frequency span from 1 Hz to 1 MHz. The system is turn-key operable, as it features an automated spatial and temporal alignment of the interferometric amplification channels
Enhancement of the Zero Phonon Line emission from a Single NV-Center in a Nanodiamond via Coupling to a Photonic Crystal Cavity
Using a nanomanipulation technique a nanodiamond with a single nitrogen
vacancy center is placed directly on the surface of a gallium phosphide
photonic crystal cavity. A Purcell-enhancement of the fluorescence emission at
the zero phonon line (ZPL) by a factor of 12.1 is observed. The ZPL coupling is
a first crucial step towards future diamond-based integrated quantum optical
devices
Elemental Bioimaging of Sheep Bone and Articular Cartilage After Single Application of Gadolinium-Based Contrast Agents
BACKGROUND: Gadolinium-based contrast agents (GBCAs) are applied to enhance magnetic resonance imaging. Gadolinium (Gd), a rare earth metal, is used in a chelated form when administered as GBCA to patients. There is an ongoing scientific debate about the clinical significance of Gd retention in tissues after administration of GBCAs. It is known that bone serves as Gd reservoir, but only sparse information on localization of Gd in bone is available.
PURPOSE: The aim of this study was to compare Gd tissue concentration and spatial distribution in femoral epiphysis and diaphysis 10 weeks after single-dose injection of linear and macrocyclic GBCAs in a large animal model.
MATERIALS AND METHODS: In this prospective animal study, Swiss-Alpine sheep (n = 36; age range, 4-10 years) received a single injection (0.1 mmol/kg) of macrocyclic (gadobutrol, gadoteridol, and gadoterate meglumine), linear (gadodiamide and gadobenate dimeglumine) GBCAs, or saline. Ten weeks after injection, sheep were killed, and femur heads and shafts were harvested. Gadolinium spatial distribution was determined in 1 sample of each treatment group by laser ablation-inductively coupled plasma-mass spectrometry. All bone specimens were analyzed histopathologically.
RESULTS: Injection of GBCAs in female Swiss-Alpine sheep (n = 36) resulted in Gd localization at the endosteal and periosteal surface and in a subset of GBCAs additionally at the cement lines and the bone cartilage junction. No histopathological alterations were observed in the investigated tissue specimens.
CONCLUSIONS: Ten weeks after single injection of a clinically relevant dose in adult sheep, both linear species of GBCA resulted in considerably higher accumulation than macrocyclic GBCAs. Gadolinium deposits were restricted to distinct bone and cartilage compartments, such as in bone linings, cement lines, and bone cartilage junctions. Tissue histology remained unaffected
Differential Glucose Uptake in Quadriceps and Other Leg Muscles During One-Legged Dynamic Submaximal Knee-Extension Exercise
One-legged dynamic knee-extension exercise (DKE) is a widely used model to study the local cardiovascular and metabolic responses to exercise of the quadriceps muscles. In this study, we explored the extent to which different muscles of the quadriceps are activated during exercise using positron emission tomography (PET) determined uptake of [18F]-fluoro-deoxy-glucose (GU) during DKE. Five healthy male subjects performed DKE at 25âW for 35âmin and both the contracting and contralateral resting leg were scanned with PET from mid-thigh and distally. On average, exercise GU was the highest in the vastus intermedius (VI) and lowest in the vastus lateralis (VL; VI vs VL, pâ<â0.05), whereas the coefficient of variation was highest in VL (VL vs VI, pâ<â0.05). Coefficient of variation between the mean values of the four quadriceps femoris (QF) muscles in the exercising leg was 35â±â9%. Compared to mean GU in QF (=100%), GU was on average 73% in VL, 84% in rectus femoris, 115% in vastus medialis, and 142% in VI. Variable activation of hamstring muscles and muscles of the lower leg was also observed. These results show that GU of different muscles of quadriceps muscle group as well as between individuals vary greatly during DKE, and suggests that muscle activity is not equal between quadriceps muscles in this exercise model. Furthermore, posterior thigh muscles and lower leg muscles are more active than hitherto thought even during this moderate exercise intensity
Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
The human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4
Patients with Acute Limb Ischemia Might Benefit from Endovascular TherapyâA 17-Year Retrospective Single-Center Series of 985 Patients
Acute lower limb ischemia (ALI) is a common vascular emergency, requiring urgent revascularization by open or endovascular means. The aim of this retrospective study was to evaluate patient demographics, treatment and periprocedural variables affecting the outcome in ALI patients in a consecutive cohort in a tertiary referral center. Primary outcome events (POE) were 30-day (safety) and 180-day (efficacy) combined mortality and major amputation rates, respectively. Secondary outcomes were perioperative medical and surgical leg-related complications and the 5-year combined mortality and major amputation rate. Statistical analysis used descriptive and uni- and multivariable Cox regression analysis. In 985 patients (71 ± 9 years, 56% men) from 2004 to 2020, the 30-day and 180-day combined mortality and major amputation rates were 15% and 27%. Upon multivariable analysis, older age (30 d: aHR 1.17; 180 d: 1.27) and advanced Rutherford ischemia stage significantly worsened the safety and efficacy POE (30 d: TASC IIa aHR 3.29, TASC IIb aHR 3.93, TASC III aHR 7.79; 180 d: TASC IIa aHR 1.97, TASC IIb aHR 2.43, TASC III aHR 4.2), while endovascular treatment was associated with significant improved POE after 30 days (aHR 0.35) and 180 days (aHR 0.39), respectively. Looking at five consecutive patient quintiles, a significant increase in endovascular procedures especially in the last quintile could be observed (17.5% to 39.5%, p < 0.001). Simultaneously, the re-occlusion rate as well as the number of patients with any previous revascularization increased. In conclusion, despite a slightly increasing early re-occlusion rate, endovascular treatment might, if possible, be favorable in ALI treatment
Prognostic Impact of Bcl-2 Depends on Tumor Histology and Expression of MALAT-1 lncRNA in NonâSmall-Cell Lung Cancer
IntroductionApoptosis is a crucial pathway in tumor growth and metastatic development. Apoptotic proteins regulate the underlying molecular cascades and are thought to modulate the tumor response to chemotherapy and radiation. However, the prognostic value of the expression of apoptosis regulators in localized nonâsmall-cell lung cancer (NSCLC) is still unclear.MethodsWe investigated the protein expression of apoptosis regulators Bcl-2, Bcl-xl, Mcl-1, and pp32/PHAPI, and the expression of the lncRNA MALAT-1 in tumor samples from 383 NSCLC patients (median age: 65.6 years; 77.5% male; paraffin-embedded tissue microarrays). For statistical analysis correlation tests, Log rank tests and Cox proportional hazard models were applied.ResultsTumor histology was significantly associated with the expression of Bcl-2, Bcl-xl and Mcl-1 (all p < 0.001). Among the tested apoptotic markers only Bcl-2 demonstrated prognostic impact (hazard ratio = 0.64, p = 0.012). For NSCLC patients with non-adenocarcinoma histology, Bcl-2 expression was associated with increased overall survival (p = 0.036). Besides tumor histology, prognostic impact of Bcl-2 was also found to depend on MALAT-1 lncRNA expression. Gene expression analysis of A549 adenocarcinoma cells with differential MALAT-1 lncRNA expression demonstrated an influence on the expression of Bcl-2 and its interacting proteins.ConclusionsBcl-2 expression was specifically associated with superior prognosis in localized NSCLC. An interaction of Bcl-2 with MALAT-1 lncRNA expression was revealed, which merits further investigation for risk prediction in resectable NSCLC patients
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