To further understand and assess clinical utility, the positive predictive value PPV and negative predictive value NPV for model prediction should be calculated Janes et al. If and only if the predictive performance for known treatment responses and outcomes is sufficiently high a conventional notion of acceptable cutoffs for predictive performance is yet to be established in the field of mathematical oncology , models may be used to simulate and predict untested treatments.
To use calibrated and validated model parameters to simulate alternative treatments, it is important to limit the exploration space to treatments that can be derived from the calibrated and validated model. Treatments that the model was not trained to predict should not be simulated. Furthermore, if, for example, the training data contain only single-dose levels and the biological dose response curves are unknown, predictions into untested doses should be met with caution and limited confidence.
While it is straightforward to simulate arbitrary treatment protocols, clinical feasibility for example, radiation therapies can rarely be delivered more than twice a day or on the weekend due to logistical constraints and biologically important bounds such as drug agent half-life or toxicity must be honored.
Additionally, when comparing predicted responses to innovative treatments with the data, one can only draw conclusions about the evaluated regimes. Mathematical oncology has contributed significant scientific insights into the dynamics of tumor growth and treatment response and is uniquely positioned to help map the multidimensional treatment response space Enderling et al. The art of the mathematical oncology profession must deploy a standard to only predict novel treatments if the model is properly trained and validated to do so.
Shortcuts to translational treatment predictions Fig. This opinion article is not meant to be a thorough review. Therefore, we selected references to illustrate our opinion and apologize to the un-cited authors who significantly contributed to and continue to contribute to the field of mathematical oncology.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Renee Brady, Email: gro. Heiko Enderling, Email: gro. Read article at publisher's site DOI : This data has been text mined from the article, or deposited into data resources. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
Seminal papers have initiated and promoted mathematical modeling of cancer and have helped define the field of mathematical oncology Norton and Simon in J Natl Cancer Inst , ; Norton in Can Res , ; Hahnfeldt et al. Bull Math Biol. Published online Jul PMID: These contributions are thankfully acknowledged. The following information was supplied relating to ethical approvals i.
The company where the experiments for this paper have been conducted uses human tissue excised skin from plastic surgery for several customer projects per month. Therefore no project-specific ethical approval is needed. The skin tissue is obtained from practices or clinics performing plastic surgery which have the permission. This is approved with the signature of the responsible surgeon. The following information was supplied regarding data availability:. Read article at publisher's site DOI : This data has been text mined from the article, or deposited into data resources.
To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Ann Anat , , 04 Apr Cited by 2 articles PMID: Dermatology , 1 , 01 Jan Cited by 20 articles PMID: J Invest Dermatol , 93 6 , 01 Dec Cited by 11 articles PMID: Pedersen G.
Free full text. Published online Oct 3. PMID: Author information Article notes Copyright and License information Disclaimer. Corresponding author. Isa Bauhammer: ed. Received Jul 3; Accepted Sep 1. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. Go to:. Supplemental Information 1: Skin cultivation measurements and calibration curve.
Supplemental Information 3: Non-parametric statistical analysis: Moods Median test with 0. Evaluation of the effect of the medium supplements on viability. Supplemental Information 4: Summary of skin cultivation measurements and calculation of viability. Supplemental Information 5: Word list translated into English The protocols in the supplementary files containing German references are locked and cannot be changed as they are validated for the Lab.
Open in a separate window. Figure 1. Graphical illustration of the sample distribution for cultivation. Figure 2. Illustration of skin cultivation samples and LDH measurement. Controls In order to quantify the highest possible LDH release from the skin of each species, a positive control was established for which a piece of skin was weighed, added to a defined amount of DMEM and mechanically destroyed with an immersion blender.
Measurement by plate reader Photometric measurement of the obtained medium samples for the quantification of LDH release into the medium was conducted with a plate reader microplate reader Wallac Victor 2 using an absorbance wavelength of nm see Fig. All calculations were performed using Microsoft Excel Data analysis Statistical evaluation was conducted using statistics software OriginPro 9. Figure 3. Comparison of the total released LDH of each species at the end of the study with the relative LDH release as percentage of the positive control of each species.
Figure 4. Viability trend of the skin samples in percent over 14 days of cultivation, comparing cultivation media. Figure 5. Viability trend of the skin samples in percent over 14 days of cultivation, comparing species. Identification of this large population of electrically coupled neurons in this classic model, and the ability to genetically manipulate these electrically synapsed neurons, expands the GF system capabilities for the nuanced, sophisticated circuit dissection necessary for deeper investigations into brain formation.
Genetic model neural circuits with individually identifiable neurons help us to understand how nervous systems wire together during development, and then operate through coordinated chemical and electrical signaling. The Drosophila giant fiber circuit has long served as such a model, due to large neuron size, genetic malleability, and easily visualized behavioral output: a jump in response to a threat.
This study unveils new members of this circuit, all of which synapse with the circuit at one site on the central giant fiber interneuron. We use new tools to identify and transgenically manipulate these neurons and show that these neurons are required for proper circuit development. This study provides a detailed circuit map for further dissection of neuronal connectivity and electrically coupled communication. The Drosophila giant fiber GF circuit is particularly suitable for single-neuron resolution neurodevelopmental studies for a number of reasons, all related to its role as an escape response circuit Allen et al.
The need for rapid signal conduction from the senses through brain to muscles promoted the evolution of very large neurons throughout this circuit, facilitating their visualization and manipulation Power, ; Borgen et al.
This enlargement is most prominent in the long-distance GF interneuron GFI , which consolidates sensory information in the brain and projects through the neck into the thoracic ganglion TG via giant axons Allen et al. To increase communication speed and fidelity between neurons, the GF circuitry uses mixed chemical and electrical synapses Thomas and Wyman, ; Blagburn et al.
These electrical synapses, composed of the Shaking-B innexin, can pass small tracer dyes to identify coupled partner neurons Phelan et al. The GF circuit targets two large muscle sets used for rapid escape behavior, the tergotrochanteral muscle TTM , which controls the legs for jumping, and the dorsal longitudinal muscle DLM , which controls the wings Tanouye and Wyman, The escape behavior is easily scored, and muscles are accessible to electrophysiological recordings, providing two outlets to study whole-circuit function Martinez et al.
While the GF circuit is reported to be quite simple, electrophoretic injections with small dyes make it clear that the GFI is actually part of a much larger circuit network of undescribed neurons Boerner and Godenschwege, ; Enneking et al.
This larger GF circuit should come as no surprise, as most classically studied circuits are continuously being updated to include new neurons, increasing the appreciation of the complexity and interconnectivity within the brain Lin et al.
Describing the wiring diagrams of classic circuits within model brains is important for understanding how local circuits accomplish processing tasks while also overriding or promoting behaviors controlled by separated but interconnected circuits Gaudry and Kristan, ; Stensmyr et al. More complex model circuits can better help to answer questions about how circuits develop and evolve over time Ward et al.
Combining GF circuit manipulability with the full complement of GFI-coupled neurons should enable robust new avenues for experimentation on how neurons select partners, determine synaptic strength, and regulate neighboring circuits. This approach defined four new GFI-coupled neuron clusters i. We show that the inframedial bridge IB; Allen et al. We ablate GF neurons by transgenic expression of the apoptotic head involution defective Hid protein Zhou et al.
We also find GFI axons always compensate for the loss of their bilaterally symmetric partner through new contralateral innervation. Together, this work broadens the known GF circuit and opens new avenues for studying electrically coupled circuit development, function, and plasticity.
Timed-lay eggs were collected for 2—3 d, and experimental animals were selected from rearing tubes 10—14 d later. Both females and males were used in this study, with sex-specific selection stated in figure legends. All genotypes were verified with visible markers.
GFI dye injections were performed similar to the previously published methods Boerner and Godenschwege, ; Kennedy and Broadie, Electrodes were filled with 0. Filled electrodes were placed on a silver chloride wire mounted on a PCS Micromanipulator Burleigh. Animals in physiologic saline were cut along the dorsal midline to access the cervical connective CC , at which electrodes were inserted into the GFI. A square-pulse stimulator Grass S48, Astro-Med provided 7. Labels were diluted in PBST with 0.
To prevent crushing, double-sided poster tape Scotch was placed on each side of the brains. Coverslips catalog 1. Fluorescent images were collected using a Zeiss LSM Confocal Microscope with an AiryScan module, which has increased lateral resolution nm and signal-to-noise ratio Sivaguru et al. Images show maximum Z -stack projections under standard confocal mode, unless otherwise noted in the figure legends.
Neuronal models and movies were created using Imaris version 9. Small gap junction-permeable dyes used to study the GF circuit have consistently revealed an extensive, but uncharacterized, network of dye-coupled neurons Boerner and Godenschwege, ; Enneking et al. To thoroughly study the architecture and properties of these neurons, we iontophoretically injected the GFI with the highly gap junction-permeable NB dye, and then labeled the brains post hoc with a streptavidin-conjugated fluorophore Huang et al.
Consistent with previously published work, this intracellular dye injection reveals an extensive network of neurons dye coupled to the GFI Fig. This dye coupling is the direct result of gap junction connectivity, as eliminating gap junctions using shaking-B mutants shakB 2 prevents all NB dye transfer data not shown; Blagburn et al. A summary of this newly identified GF circuitry is shown in Figure 1.
Giant fiber interneuron dye injection reveals coupled neurons. Although there are a large number of dye-labeled processes widely distributed throughout the TG Fig. Here, we map and characterize all of the dye-coupled neurons whose projections we can trace back to an identifiable cell soma. We have named these neurons GFC followed by an identifying number Fig.
In this study, we report the characterization of four neuron clusters GFC1—4 , each of which represents a bilaterally symmetric set of two to seven neurons Fig. To understand how the GFCs integrate into the GF circuit, we began by obtaining selective genetic access to these neurons. To accurately map and manipulate the separate GFC neuron populations, we set forth to identify Gal4 drivers with highly specific expression for each GFC using two approaches.
First, we conducted an in silico screen through the entire Janelia FlyLight library, which includes lines generated from the Vienna Tiles project lines; Jenett et al. Using images of the GFI dye-labeled circuit Fig. During our search with the MIP tool, we identified many additional GF circuit drivers, aside from the ones used in this study. We selected the cleanest drivers and report them in Table 1 for use in future experiments. Transgenic Gal4 drivers for the newly identified GFC neurons.
The GFC neurons are drawn both in color Fig. TG segments are selected to best show GFC projection architecture. All injections were performed on females. The driver strength is relatively weak, with a somewhat stochastic labeling of the GFC1 neurons.
This driver is moderately strong, but also labels other neurons. This driver strength is moderate, with labeling of other neurons. Cite this: Chem. Article Views Free 3D Models. Free Wallpaper. Personalized wooden cabinet 3d model. Black simple desk 3d model. Southeast Asian wooden dresser 3d model. European yellow bedside cabinet 3d model. The oxygen reduction reaction ORR has a key role in metal-air batteries and polymer membrane electrolyte fuel cells 1 , 2 , but has become a bottleneck.
ORRs traditionally require the exclusive use of platinum-based catalysts 3 , 4. Owing to the high cost of Pt and declining activity, alternative catalysts based on non-precious metal oxides, for example, Fe 3 O 4 , Co 3 O 4 and so on, have been actively pursued 5 , 6 , 7 , 8 , 9 , 10 , TiO 2 is a widely used semiconductor because of its Earth abundance, low cost, no toxicity and high stability Thus, incorporating TiO 2 into energy conversion and storage systems is thus an attractive and promising idea.
Up to now, several works have been reported on the use of TiO 2 for ORR, but an overall low activity is obtained 12 , 13 , 14 , 15 , 16 , 17 , 18 , Tremendous efforts have been made to improve TiO 2 electrochemical properties. The non-stoichiometric reduction of TiO 2 is known to substantially narrow the bandgap to the semiconductor level usually below 2.
The surface atomic structure, physiochemical properties and catalytic activity of TiO 2 are also highly shape- and facet-dependent The lattice fringe spacing of 0.
Moreover, the angle labelled in the corresponding fast-Fourier transform image inset was Then, TiO 2 was formed with these complexes as intermediates reaction 2. These mesopores were constructed by gathering nanoparticles into nanosheets, and the Brunauer—Emmett—Teller BET surface area was calculated as The cathodic current was also much higher on the facet- and defect-engineered TiO 2 sample Supplementary Table 1.
Linear sweep voltammetry in O 2 -saturated 0. The number of transferred electrons in ORR, n , was calculated from the slopes of straight lines at different potentials using the Koutecky—Levich model Supplementary Figs 6 and 7 , and a continuous increase in n with the increasing overpotential was observed. Specifically, the calculated electron transfer number, n , was 0. The calculated electron transfer number, n , from the RRDE tests varied in a range of 1.
Considering the low electric conductivity and poor dispersity of nano-sized metal oxide catalysts, some nano-structured carbonaceous supports are usually needed in ORR tests Interactions between rGO and metal oxide indicate a possible charge transfer across the interface depending on the hybrid interface spacing and the Fermi level difference, which might be the main reason for the enhanced ORR activity 10 , Moreover, all TiO 2 samples showed superior selectivity to ORR with no obvious current change after adding methanol.
The above results clearly show that the ORR activity of TiO 2 was substantially enhanced by a simple facet- and defect-engineering strategy. Moreover, TiO 2 is intrinsically characterized of Earth abundance, low cost, high stability and environmental compatibility for industrial applications. In high-resolution XPS, an obvious shoulder appeared in the low-energy range Moreover, the measured Raman spectra also confirmed the presence of more oxygen vacancies in the reduced TiO 2 SCs, owing to the positive peak shift, which was resulted from the modified geometric and surface structures Fig.
Lowering the electrochemical overpotentials for both hydrogen evolution reaction HER and oxygen evolution reaction OER favours their efficient applications.
The ORR is affected by the chemical composition, elemental valence, crystal structure and surface state 5 , 6 , 7 , 8 , 9 , 10 , Also, the adsorption configuration of surface oxygen molecule and the corresponding strength of oxygen binding also impact with the ORR activities.