The example shows the learned IT map with high w =2 0 approximating the ET map.

In many unpaired image domain translation problems, e.g., style transfer or super-resolution, it is important to keep the translated image similar to its respective input image.

State-of-art methods learn the correspondence using large numbers of unpaired examples from both domains and are based on generative adversarial networks.

We cannot thank the reviewers enough for their valuable feedback on our work. Reviewers 1 and 2: Combine guess loss with additive noise. Most recent advances in adversarial defense methods address "black-box attacks" performed by a The latter incorporates adversarial examples during training to increase the model's robustness to the attack. Therefore the reconstructed image can serve as an adversarially perturbed example of the non-adversarial input image. Reviewer 3: Novelty is not enough as most of the proposed solution or observations are already published.

Image registration refers to the process of spatially aligning two or more images by mapping them into a common coordinate system, so that corresponding anatomical or tissue structures are matched across images. In digital pathology, registration enables direct comparison and integration of information from different stains or imaging modalities, sup-porting applications such as biomarker analysis and tissue reconstruction. Accurate registration of images from different modalities is an essential step in digital pathology. In this study, we investigated how various color transformation techniques affect image registration between hematoxylin and eosin (H&E) stained images and non-linear multimodal images. We used a dataset of 20 tissue sample pairs, with each pair undergoing several preprocessing steps, including different color transformation (CycleGAN, Macenko, Reinhard, Vahadane), inversion, contrast adjustment, intensity normalization, and denoising. All images were registered using the VALIS registration method, which first applies rigid registration and then performs non-rigid registration in two steps on both low and high-resolution images. Registration performance was evaluated using the relative Target Registration Error (rTRE). We reported the median of median rTRE values (MMrTRE) and the average of median rTRE values (AMrTRE) for each method. In addition, we performed a custom point-based evaluation using ten manually selected key points. Registration was done separately for two scenarios, using either the original or inverted multimodal images. In both scenarios, CycleGAN color transformation achieved the lowest registration errors, while the other methods showed higher errors. These findings show that applying color transformation before registration improves alignment between images from different modalities and supports more reliable analysis in digital pathology.

Lightweight deep learning models offer substantial reductions in computational cost and environmental impact, making them crucial for scientific applications. We present a lightweight CycleGAN for modality transfer in fluorescence microscopy (confocal to super-resolution STED/deconvolved STED), addressing the common challenge of unpaired datasets. By replacing the traditional channel-doubling strategy in the U-Net-based generator with a fixed channel approach, we drastically reduce trainable parameters from 41.8 million to approximately nine thousand, achieving superior performance with faster training and lower memory usage. We also introduce the GAN as a diagnostic tool for experimental and labeling quality. When trained on high-quality images, the GAN learns the characteristics of optimal imaging; deviations between its generated outputs and new experimental images can reveal issues such as photobleaching, artifacts, or inaccurate labeling. This establishes the model as a practical tool for validating experimental accuracy and image fidelity in microscopy workflows.

The example shows the learned IT map with high w =2 0 approximating the ET map.

In many unpaired image domain translation problems, e.g., style transfer or super-resolution, it is important to keep the translated image similar to its respective input image.

The mechanosensory system of teeth is currently believed to partly rely on Odontoblast cells stimulation by fluid flow through a porosity network extending through dentin. Visualizing the smallest sub-microscopic porosity vessels therefore requires the highest achievable resolution from confocal fluorescence microscopy, the current gold standard. This considerably limits the extent of the field of view to very small sample regions. To overcome this limitation, we tested different deep learning (DL) super-resolution (SR) models to allow faster experimental acquisitions of lower resolution images and restore optimal image quality by post-processing. Three supervised 2D SR models (RCAN, pix2pix, FSRCNN) and one unsupervised (CycleGAN) were applied to a unique set of experimentally paired high- and low-resolution confocal images acquired with different sampling schemes, resulting in a pixel size increase of x2, x4, x8. Model performance was quantified using a broad set of similarity and distribution-based image quality assessment (IQA) metrics, which yielded inconsistent results that mostly contradicted our visual perception. This raises the question of the relevance of such generic metrics to efficiently target the specific structure of dental porosity. To resolve this conflicting information, the generated SR images were segmented taking into account the specific scales and morphology of the porosity network and analysed by comparing connected components. Additionally, the capacity of the SR models to preserve 3D porosity connectivity throughout the confocal image stacks was evaluated using graph analysis. This biology-driven assessment allowed a far better mechanistic interpretation of SR performance, highlighting differences in model sensitivity to weak intensity features and the impact of non-linearity in image generation, which explains the failure of standard IQA metrics.