When you give a code 'for free' after a person buys a product that is not 'for free'. That requires the purchase of a product. And in any event, even if it were for free, it is still a violation of 3.1.1.
Or would it be more applicable to use the activation codes for access to a group, which then provides access to the app content?( -app-store-revenue-keep-a-bigger-piece-of-the-pie-with-web-based-purchases)
Spine Activation Code Free
The app would be primarily advertised by the activation codes and their operation manual. This way there would be no implicit or explicit advertisement of purchasing methods other than the in-app purchase.
if by 'only' you mean it would do nothing other than 'grant access' then you are only reading the content and might be a reader app. But if you mean 'the app will do nothing else' then no, the activation code is needed to enable the app's code to operate.
Accurate vertebra localization and identification are required in many clinical applications of spine disorder diagnosis and surgery planning. However, significant challenges are posed in this task by highly varying pathologies (such as vertebral compression fracture, scoliosis, and vertebral fixation) and imaging conditions (such as limited field of view and metal streak artifacts). This paper proposes a robust and accurate method that effectively exploits the anatomical knowledge of the spine to facilitate vertebra localization and identification. A key point localization model is trained to produce activation maps of vertebra centers. They are then re-sampled along the spine centerline to produce spine-rectified activation maps, which are further aggregated into 1-D activation signals. Following this, an anatomically-constrained optimization module is introduced to jointly search for the optimal vertebra centers under a soft constraint that regulates the distance between vertebrae and a hard constraint on the consecutive vertebra indices. When being evaluated on a major public benchmark of 302 highly pathological CT images, the proposed method reports the state of the art identification (id.) rate of 97.4%, and outperforms the best competing method of 94.7% id. rate by reducing the relative id. error rate by half.
A key feature of signalling in dendritic spines is the synapse-specific transduction of short electrical signals into biochemical responses. Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger. Upon action potential firing, the majority of spines are subject to global back-propagating action potential (bAP) Ca2+ transients. These transients translate neuronal suprathreshold activation into intracellular biochemical events. Using a combination of electrophysiology, two-photon Ca2+ imaging, and modelling, we demonstrate that bAPs are electrochemically coupled to Ca2+ release from intracellular stores via ryanodine receptors (RyRs). We describe a new function mediated by spine RyRs: the activity-dependent long-term enhancement of the bAP-Ca2+ transient. Spines regulate bAP Ca2+ influx independent of each other, as bAP-Ca2+ transient enhancement is compartmentalized and independent of the dendritic Ca2+ transient. Furthermore, this functional state change depends exclusively on bAPs travelling antidromically into dendrites and spines. Induction, but not expression, of bAP-Ca2+ transient enhancement is a spine-specific function of the RyR. We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines. Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns.
Experiences change neuronal circuits, and these circuit changes outlast the initial experiences. This means that, in neurons, the fast electrical activity encoding experiences needs to be transduced into longer-lived biochemical and structural changes. A key mediator between these two timescales of neuronal activity is the Ca2+ ion. Ca2+ serves both as an electric charge carrier mediating fast voltage changes at the membrane and as a second messenger activating intracellular signalling cascades. Even within the spatial confines of dendritic spines, the specialized domains of dendrites that receive synaptic connections, Ca2+ encodes a versatile array of specific functions. In this study, we first demonstrate that voltage-gated Ca2+ channels and ryanodine receptors, intracellular channels located on the membrane of the endoplasmic reticulum through which Ca2+ can be released into the cytosol, are electrochemically coupled in single dendritic spines. We identify how ryanodine receptors induce enhancement of the Ca2+ influx, mediated by the opening of voltage-gated Ca2+ channels, induced by action potentials in a compartmentalized, spine-specific manner. Within the femtoliter volume of a single spine, specificity of this route of Ca2+-signalling is achieved by a signalling nanodomain centred on the ryanodine receptor. Our work stresses the role of the ryanodine receptor not only as an ion channel releasing Ca2+ from the endoplasmic reticulum but also as a macromolecular complex generating specificity of Ca2+-signalling within the spatial constraints of a single spine.
Spine Ca2+ influx via the plasma membrane is mediated by N-methyl-D-aspartate receptors (NMDARs) and voltage gated Ca2+ channels (VGCCs). Suprathreshold neuronal activity, resulting in action potential (AP) firing, produces two different activation modes for spine Ca2+ influx. A subset of spines receives local synaptic input evoked by excitatory synaptic transmission, resulting in NMDAR- and VGCC- mediated Ca2+ influx [5]. Per given suprathreshold activation sequence, the majority of spines, however, do not receive specific synaptic activation. In these spines, depolarization mediated by back-propagating APs (bAPs) activates VGCCs. This signalling mode is independent of presynaptic input and affects a large population of spines throughout the dendritic tree [6]. To date, this unspecific, bAP-mediated signalling mode is poorly understood.
We studied the activity-dependent temporal dynamics of bAP-Ca2+ transients in spines that do not receive specific synaptic inputs but undergo unspecific activation by bAPs in excitatory cortical and hippocampal neurons. We describe a new compartmentalized plastic change of a spine's functional state: the suprathreshold activity-dependent enhancement of bAP-Ca2+ transients. The induction of enhancement in spines requires RyR mediated Ca2+ release that is organized in a functional nanodomain.
Next, we wanted to test if a further reduction in neuronal output could abolish enhancement and whether doublet firing is required. We reduced the putative induction stimulus to three single bAPs (Fig 4C). Single AP stimulation was then continued after a 10 min stimulus-free interval (Fig 4B). The further reduction in bAP number and frequency abolished enhancement (Fig 4D). We even observed a small depression, which was significant when tested against a theoretical median of 0% change (p 20% was reached in about 60% of spines in the small baseline bAP-Ca2+ transient amplitude. When omitting the 5 AP bursts, enhancement >20% was only observed in 40% of spines.
Most likely, bAP-mediated cytoplasmic Ca2+ elevations are the biochemical link between the induced membrane depolarization and downstream signal transduction events that result in enhancement. To test for an inductive role of free Ca2+, we again used 500 μM of the medium-affinity Ca2+ indicator fluo-5F, this time with an experimental protocol identical to the one that induces significant enhancement with fluo-4FF. At this concentration, free cytosolic Ca2+ is strongly buffered, permitting a linear readout of the spine Ca2+ flux while simultaneously reducing the activation of transduction cascades by intra-spine free Ca2+ (added buffer capacity kdye of 350 for 500 μM fluo-5F according to Yasuda et al., 2004 [23]). Indeed, enhancement was blocked in the whole spine population measured with 500 μM fluo-5F (-10 3%, n = 68/24 spines/cells; whole population 200 μM fluo-4FF: +19 4%, n = 92/43 spines/cells; p
Using 500 μM fluo-5F, the Gmax/R value under saturating [Ca2+] was at 1.34 0.2 (see above and Methods for details). We infer that activity dependent enhancement requires sufficient free intraspine Ca2+.
We next asked whether the contribution of stores to bAP-Ca2+ transient enhancement results from store activation during induction or whether store activation underlies the expression of enhancement. To test the hypothesis that the expression of bAP-Ca2+ transient enhancement is mediated by recruitment of intracellular Ca2+ stores, 30 μM CPA was washed in after 15 min. This permitted to assess enhancement during our defined time interval for quantification of enhancement (Fig 3C) without an appreciable effect of CPA, as Fig 1C demonstrates that the first 5 min of CPA wash-in did not have an effect. We preselected for enhanced spines (enhancement >20% between 15 and 20 min after starting the experiment; as doublet application has been demonstrated to be sufficient in inducing enhancement, some enhancement can already be observed at the end of our 6 min baseline measurement when only the enhanced spines are plotted). In enhanced spines, 10 min of CPA application resulted in a small reduction of enhancement which was not significant when compared to enhanced control spines in the same time interval (Fig 7B). From Fig 1C, we can see that this 10 min wash-in of CPA already has a significant effect on the bAP-Ca2+ transient measured with 500 μM fluo-5F (CPA: -18 3%, n = 17/3 spines/cells; control: +6 5%, n = 13/3 spines/cells, p 2ff7e9595c
Comentários