•Performance of different sparsity constraints for audio inpainting are evaluated.•Adaptive time-frequency representations significantly improve inpainting results.•Neighborhood based sparsity ...approaches further improve perceptual quality.•Numerical evaluations are based on eight audio signals of various characteristics.
Audio signals such as music are known to exhibit distinct and sparse time-frequency patterns. In particular, the short-time Fourier/Gabor transform is widely used for sparsely representing audio signals. In this contribution, such sparsity patterns are exploited to reconstruct missing samples. The quality of reconstruction is evaluated for various kinds of proximal splitting algorithms, time-frequency discretizations and sparsity enforcing constraints. Furthermore, given a time-frequency representation, we investigate the performance of synthesis vs. analysis approaches to the reconstruction problem. The equidistant discretization scheme of Gabor transforms is non-adaptive. It is plausible, that more flexible time-frequency representations like wavelets or ERBlets improve reconstruction of missing audio samples. The numerical results presented in this contribution confirm this conjecture and lead to good reconstruction results even for gaps of contiguously missing samples, whose size is notably larger than reported for inpainting experiments carried out previously.
Aberrant Wnt regulation, detectable by nuclear translocation of beta‐catenin, is a hallmark of many cancers including skin squamous cell carcinomas (SCCs). By analyzing primary human skin SCCs, we ...demonstrate that nuclear beta‐catenin is not restricted to SCC cells but also detected in stromal fibroblasts, suggesting an important role for aberrant Wnt regulation also in the tumor microenvironment. When human keratinocytes and fibroblasts were treated with Wnt‐3a, fibroblasts proved to be more responsive. Accordingly, Wnt‐3a did not alter HaCaT cell functions in a cell‐autonomous manner. However, when organotypic cultures (OTCs) were treated with Wnt‐3a, HaCaT keratinocytes responded with increased proliferation. As nuclear beta‐catenin was induced only in the fibroblasts, this argued for a Wnt‐dependent, paracrine keratinocyte stimulation. Global gene expression analysis of Wnt‐3a‐stimulated fibroblasts identified genes encoding interleukin‐8 (IL‐8) and C‐C motif chemokine 2 (CCL‐2) as well as matrix metalloproteinase‐1 (MMP‐1) as Wnt‐3a targets. In agreement, we show that IL‐8 and CCL‐2 were secreted in high amounts by Wnt‐3a‐stimulated fibroblasts also in OTCs. The functional role of IL‐8 and CCL‐2 as keratinocyte growth regulators was confirmed by directly stimulating HaCaT cell proliferation in conventional cultures. Most important, neutralizing antibodies against IL‐8 and CCL‐2 abolished the Wnt‐dependent HaCaT cell hyperproliferation in OTCs. Additionally, MMP‐1 was expressed in high amounts in Wnt‐3a‐stimulated OTCs and degraded the stromal matrix. Thus, our data show that Wnt‐3a stimulates fibroblasts to secrete both keratinocyte proliferation‐inducing cytokines and stroma‐degrading metalloproteinases, thereby providing evidence for a novel Wnt deregulation in the tumor‐stroma directly contributing to skin cancer progression.
What's new?
The Wnt signaling pathway plays a role in many cancers. The central player in this pathway is beta‐catenin; when this protein is knocked out, tumors wither and cancer stem cells disappear. In this study, the authors found beta‐catenin hanging out in the stromal fibroblasts of a quarter of skin carcinomas. The authors further showed that an active Wnt pathway in the fibroblasts would turn on various growth‐promoting elements, including chemokines IL‐8 and CCL‐2, and matrix‐degrading metalloproteinases. These results suggest that activation of the Wnt pathway in the tumor microenvironment helps spur the growth and spread of skin cancer.
Ageing, the progressive functional decline of virtually all tissues, affects numerous living organisms. Main phenotypic alterations of human skin during the ageing process include reduced skin ...thickness and elasticity which are related to extracellular matrix proteins. Dermal fibroblasts, the main source of extracellular fibrillar proteins, exhibit complex alterations during in vivo ageing and any of these are likely to be accompanied or caused by changes in gene expression. We investigated gene expression of short term cultivated in vivo aged human dermal fibroblasts using RNA-seq. Therefore, fibroblast samples derived from unaffected skin were obtained from 30 human donors. The donors were grouped by gender and age (Young: 19 to 25 years, Middle: 36 to 45 years, Old: 60 to 66 years). Two samples were taken from each donor, one from a sun-exposed and one from a sun-unexposed site. In our data, no consistently changed gene expression associated with donor age can be asserted. Instead, highly correlated expression of a small number of genes associated with transforming growth factor beta signalling was observed. Also, known gene expression alterations of in vivo aged dermal fibroblasts seem to be non-detectable in cultured fibroblasts.
Skin, as the largest organ, has long been subject of excellent and pioneering studies on stem cells and their role in tissue regulation and tumor formation. In particular, intensive research on mouse ...skin, and here especially the hair follicle, has largely extended our knowledge. Surprisingly, human skin, although the most easily accessible tissue in man, is far less conceived with regard to its stem cells and their specific environment (the niche). In consequence, these features are as yet only insufficiently defined and it still has to be elucidated how insights in cutaneous stem cell biology gained in mice can be extrapolated to humans. In the last few years, human model systems such as humanized mice or in vitro organotypic cultures that support maintenance or reconstruction of human skin and long-term epidermal regeneration have been developed. These models allow lineage tracing experiments and can be modified by adopting genetically manipulated cell types. Accordingly, they represent proper tools for human stem cell research and will clearly help to improve our still incomplete understanding. Like normal skin, the non-melanoma skin cancers and their respective tumors have gained considerable interest in basic as well as in clinical research. Being the most frequent human tumors globally, basal cell carcinomas and cutaneous squamous cell carcinomas (SCCs) continue to increase in incidence and specifically SCCs predominate in immunosuppressed transplant recipients. This review intends to compile the present knowledge on keratinocyte stem cells and their niches in normal skin and skin carcinomas with a special focus on the human situation. In particular, the role of the microenvironment, the niche, is emphasized, promoting our view of the decisive importance of the niche as a key regulatory element for controlling position, fate and regenerative potential of the stem cell population both in healthy skin and in carcinomas.
MALDI mass spectrometry imaging (MALDI MSI) is a spatially resolved analytical tool for biological tissue analysis by measuring mass-to-charge ratios of ionized molecules. With increasing spatial and ...mass resolution of MALDI MSI data, appropriate data analysis and interpretation is getting more and more challenging. A reliable separation of important peaks from noise (aka peak detection) is a prerequisite for many subsequent processing steps and should be as accurate as possible. We propose a novel peak detection algorithm based on sparse frame multipliers, which can be applied to raw MALDI MSI data without prior preprocessing. The accuracy is evaluated on a simulated data set in comparison with state-of-the-art algorithms. These results also show the proposed method's robustness to baseline and noise effects. In addition, the method is evaluated on real MALDI-TOF data sets, whereby spatial information can be included in the peak picking process.
The field of proteomics, in particular MALDI Imaging, encompasses huge amounts of data. The processing and preprocessing of this data in order to segment or classify spatial structures of certain peptides or isotope patterns can hence be cumbersome and includes several independent processing steps. In this work, we propose a simple peak-picking algorithm to quickly analyze large raw MALDI Imaging data sets, which has a better sensitivity than current state-of-the-art algorithms. Further, it is possible to get an overall overview of the entire data set showing the most significant and spatially localized peptide structures and, hence, contributes all data driven evaluation of MALDI Imaging data.
Display omitted
•Peak Picking is still a crucial task in preprocessing MALDI imaging data.•Our algorithm combines spectra and spatial information into a single process.•Evaluation is based on state-of-the-art algorithms and synthetic and real data sets.•Results show that a prior baseline removal and normalization is not needed.•m/z images after peak picking can reveal hidden spatial peptide structures.
Spike detection from extracellular recordings is a crucial preprocessing step when analyzing neuronal activity. The decision whether a specific part of the signal is a spike or not is important for ...any kind of other subsequent preprocessing steps, like spike sorting or burst detection in order to reduce the classification of erroneously identified spikes. Many spike detection algorithms have already been suggested, all working reasonably well whenever the signal-to-noise ratio is large enough. When the noise level is high, however, these algorithms have a poor performance.
In this paper we present two new spike detection algorithms. The first is based on a stationary wavelet energy operator and the second is based on the time-frequency representation of spikes. Both algorithms are more reliable than all of the most commonly used methods.
The performance of the algorithms is confirmed by using simulated data, resembling original data recorded from cortical neurons with multielectrode arrays. In order to demonstrate that the performance of the algorithms is not restricted to only one specific set of data, we also verify the performance using a simulated publicly available data set. We show that both proposed algorithms have the best performance under all tested methods, regardless of the signal-to-noise ratio in both data sets.
This contribution will redound to the benefit of electrophysiological investigations of human cells. Especially the spatial and temporal analysis of neural network communications is improved by using the proposed spike detection algorithms.
The BRAF inhibitor vemurafenib, approved for treating patients with BRAF V600E-mutant and unresectable or metastatic melanomas, rapidly induces cutaneous adverse events, including hyperkeratotic skin ...lesions and cutaneous squamous cell carcinomas (cSCC). To determine, how vemurafenib would provoke these adverse events, we utilized long-term
skin equivalents (SEs) comprising epidermal keratinocytes and dermal fibroblasts in their physiological environment. We inserted keratinocytes with different genetic background normal keratinocytes: NHEK, HaCaT (p53/mut), and HrasA5 (p53/mut+Hras/mut) to analyze effects depending on the stage of carcinogenesis. We now show that vemurafenib activates MEK-ERK signaling in both, keratinocytes, and fibroblasts
and in the
-like SEs. As a consequence, vemurafenib does not provide a growth advantage but leads to a differentiation phenotype, causing accelerated differentiation and hyperkeratosis in the NHEK and normalized stratification and cornification in the transformed keratinocytes. Although all keratinocytes responded very similarly to vemurafenib in their expression profile, particularly with a significant induction of MMP1 and MMP3, only the HrasA5 cells revealed a vemurafenib-dependent pathophysiological shift to tumor progression, i.e., the initiation of invasive growth. This was shown by increased proteolytic activity allowing for penetration of the basement membrane and invasion into the disrupted underlying matrix. Blocking MMP activity, by the addition of ilomastat, prevented invasion with all corresponding degradative activities, thus substantiating that the RAS-RAF-MEK-ERK/MMP axis is the most important molecular basis for the rapid switch towards tumorigenic conversion of the HrasA5 keratinocytes upon vemurafenib treatment. Finally, cotreatment with vemurafenib and the MEK inhibitor cobimetinib prevented MEK-ERK hyperactivation and with that abolished both, the epidermal differentiation and the tumor invasion phenotype. This suggests that both cutaneous adverse events are under direct control of vemurafenib-dependent MEK-ERK hyperactivation and confirms the dependence on preexisting genetic alterations of the skin keratinocytes that determine the basis towards induction of tumorigenic progression.
In this contribution we deal with the problem of producing “reasonable” data, when considering recorded energy consumption data, which are at certain sections incomplete and/or erroneous. This task ...is important, when energy providers employ prediction models for expected energy consumption, which are based on past recorded consumption data, which then of course should be reliable and valid. In a related contribution Yilmaz (2022), GAN-based methods for producing such “artificial data” have been investigated. In this contribution, we describe an alternative and complementary method based on signal inpainting, which has been successfully applied to audio processing Lieb and Stark (2018). After giving a short overview of the theory of proximity-based convex optimization, we describe and adapt an iterative inpainting scheme to our problem. The usefulness of this approach is demonstrated by analyzing real-world-data provided by a German energy supplier.
Microsatellite-unstable (MSI) tumours show a high load of mutational neoantigens, as a consequence of DNA mismatch repair deficiency. Consequently, MSI tumours commonly present with dense immune ...infiltration and develop immune evasion mechanisms. Whether improved lymphocyte recruitment contributes to the pronounced immune infiltration in MSI tumours is unknown. We analysed the density of high endothelial venules (HEV) and postcapillary blood vessels specialised for lymphocyte trafficking, in MSI colorectal cancers (CRC).
HEV density was determined by immunohistochemical staining of FFPE tissue sections from MSI (n = 48) and microsatellite-stable (MSS, n = 35) CRCs. Associations with clinical and pathological variables were analysed.
We found elevated HEV densities in MSI compared with MSS CRCs (median 0.049 vs 0.000 counts/mm
, respectively, p = 0.0002), with the highest densities in Lynch syndrome MSI CRCs. Dramatically elevated HEV densities were observed in B2M-mutant Lynch syndrome CRCs, pointing towards a link between lymphocyte recruitment and immune evasion (median 0.485 vs 0.0885 counts/mm
in B2M-wild-type tumours, p = 0.0237).
Our findings for the first time indicate a significant contribution of lymphocyte trafficking in immune responses against MSI CRC, particularly in the context of Lynch syndrome. High HEV densities in B2M-mutant tumours underline the significance of immunoediting during tumour evolution.
Understanding intrathymic T cell differentiation has been greatly aided by the development of various reductionist in vitro models that mimic certain steps/microenvironments of this complex process. ...Most models focused on the faithful in vitro restoration of T cell differentiation and selection. In contrast, suitable in vitro models emulating the developmental pathways of the two major thymic epithelial cell lineages--cortical thymic epithelial cells and medullary thymic epithelial cells (mTECs)--are yet to be developed. In this regard, lack of an in vitro model mimicking the developmental biology of the mTEC lineage has hampered the molecular analysis of the so-called "promiscuous expression" of tissue-restricted genes, a key property of terminally differentiated mTECs. Based on the close biological relationship between the skin and thymus epithelial cell compartments, we adapted a three-dimensional organotypic coculture model, originally developed to provide a bona fide in vitro dermal equivalent, for the culture of isolated mTECs. This three-dimensional model preserves key features of mTECs: proliferation and terminal differentiation of CD80(lo), Aire(-) mTECs into CD80(hi), Aire(+) mTECs; responsiveness to RANKL; and sustained expression of FoxN1, Aire, and tissue-restricted genes in CD80(hi) mTECs. This in vitro culture model should facilitate the identification of molecular components and pathways involved in mTEC differentiation in general and in promiscuous gene expression in particular.
PDF
