Search

Abstract Background Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. Methods In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. Results The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter’s poor selectivity. Conclusion These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.

Abstract Background Exercise stress echocardiography is clinically used to assess cardiovascular diseases. For accurate cardiac evaluation, a stable field-of-view is required. However, transducer orientation and position are difficult to preserve. Hands-free acquisitions might provide more consistent and reproducible results. In this study, the field-of-view stability and variability of hands-free acquisitions are objectively quantified in a comparison with manually obtained images, based on image structural and feature similarities. In addition, the feasibility and consistency of hands-free strain imaging is assessed. Methods In twelve healthy males, apical and parasternal images were acquired hands-free, using a fixation device, and manually, during semi-supine exercise sessions. In the final ten seconds of every exercise period, the image structural similarity and cardiac feature consistency were computed using a steerable pyramid employing complex, oriented wavelets. An algorithm discarding images displaying lung artifacts was created. Hands-free strain consistency was analyzed. Results Hands-free acquisitions were possible in 9 of the 12 subjects, whereas manually 10 out of 12 could be imaged. The image structural similarity was significantly improved in the hands-free apical window acquisitions (0.91 versus 0.82), and at least equally good in the parasternal window (0.90 versus 0.82). The change in curvature and orientation of the interventricular septum also appeared to be lower in the hands-free acquisitions. The variability in field-of-view was similar in both acquisitions. Longitudinal, septal strain was shown to be at least as consistent when obtained hands-free compared to manual acquisitions. Conclusions The field-of-view was shown to be more or equally stable and consistent in the hands-free data in comparison to manually obtained images. The variability was similar, thus respiration- and exercise-induced motions were comparable for manual and hands-free acquisitions. Additionally, the feasibility of hands-free strain has been demonstrated. Furthermore, the results suggest the hands-free measurements to be more reproducible, though further analysis is required.

Abstract Insufficient reproduction as a consequence of predation on eggs and chicks is a major determinant of population decline in ground‐nesting birds, including waders. For many populations, there is an urgent need to maintain breeding populations at key sites, and conservation practitioners need to find viable management solutions to reduce predation. One tool available to the practitioner is fences that exclude key predators from areas containing breeding birds. Temporary electric fencing is an increasingly popular predator exclusion intervention, but such fences have costs associated with purchase and the time needed to erect and maintain them. Their effectiveness and optimal application are also frequently questioned. We evaluate the use of temporary ditch‐side four‐strand electric fences in lowland grasslands in two countries, The Netherlands and England, in areas containing high densities of breeding waders. In both countries and in all years, godwit and lapwing nest survival was significantly higher within areas enclosed by ditch‐side electric fences. Brood survival, assessed for godwits in The Netherlands, was also higher within fenced areas in all years. This demonstrates that using temporary electric fences to enclose ground‐nesting birds can be an effective tool for improving breeding productivity. In our study, closely managed electric fences were effective at excluding red foxes Vulpes vulpes, but not avian and other mammalian predators. The positive effect that electric fencing had on nest and brood survival therefore likely results from a reduction in the total number of visits by mammalian predators, and especially visits by foxes. Although it requires a substantial time investment throughout the period of use, our temporary electric fence design provides flexibility compared to other fence designs when it comes to enclosing different areas within a season and between years, as the targets for protection change or as land and flood management dictate. This conservation intervention can help buy the time required to develop and implement longer term solutions for application at larger scales.

Dynamic imaging of the skeletal muscles used to be strenuous and often impossible to perform manually. Accordingly, long-term dynamic musculoskeletal imaging has not been performed. The feasibility of long-term dynamic musculoskeletal functional analysis using hands-free ultrasound will be demonstrated in ten healthy endurance runners. After every kilometer, the vastus lateralis muscle was imaged whilst running using a fixated probe connected to a smart phone. The image quality was quantified by estimation of the probe-skin contact preservation and the field-of-view stability. Moreover, the pennation angles and muscle thicknesses were computed automatically. Long-term dynamic acquisition was successful in nine out of ten runners. Probe-skin contact loss ranged between 0 and 57% of the gait cycle. The biggest change in field-of-view occurred during the first kilometer with an average decline in complex-wavelet structural similarity index of 0.21, followed by an onward total decrease of 0.09, on average. The mean pennation angle and thickness were approximately constant, with the average fluctuation being 0.94 degrees and 0.11 cm, respectively. The feasibility of long-term musculoskeletal function analysis has been demonstrated, with probe-skin contact loss the main limiting factor. Dynamic, hands-free ultrasound might enable research for a more profound insight in the prevention and rehabilitation of musculoskeletal injuries.

Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.