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Abnormal protein aggregation has been intensively studied for over 40 years and broadly discussed in the literature due to its significant role in neurodegenerative diseases etiology. Structural reorganization and conformational changes of the secondary structure upon the aggregation determine aggregation pathways and cytotoxicity of the aggregates, and therefore, numerous analytical techniques are employed for a deep investigation into the secondary structure of abnormal protein aggregates. Molecular spectroscopies, including Raman and infrared ones, are routinely applied in such studies. Recently, the nanoscale spatial resolution of tip-enhanced Raman and infrared nanospectroscopies, as well as the high sensitivity of the surface-enhanced Raman spectroscopy, have brought new insights into our knowledge of abnormal protein aggregation. In this review, we order and summarize all nano- and micro-spectroscopic marker bands related to abnormal aggregation. Each part presents the physical principles of each particular spectroscopic technique listed above and a concise description of all spectral markers detected with these techniques in the spectra of neurodegenerative proteins and their model systems. Finally, a section concerning the application of multivariate data analysis for extraction of the spectral marker bands is included.

Genomic alterations are the driving force behind pancreatic cancer (PC) tumorigenesis, but they do not fully account for its diverse phenotypes. Investigating the epigenetic landscapes of PC offers a more comprehensive understanding and could identify targeted therapies that enhance patient survival. In this study, we have developed a new promising methodology of spatial epigenomics that integrates multiplexed molecular imaging with convolutional neural networks. Then, we used it to map epigenetic modification levels in the six most prevalent PC subtypes. We analyzed and semi-quantified the resulting molecular data, revealing significant variability in their epigenomes. DNA and histone modifications, specifically methylation and acetylation, were investigated. Using the same technique, we examined DNA conformational changes to further elucidate the transcriptional regulatory mechanisms involved in PC differentiation. Our results revealed that the foamy-gland and squamous-differentiated subtypes exhibited significantly increased global levels of epigenetic modifications and elevated Z-DNA ratios. Overall, our findings may suggest a potentially reduced efficacy of therapeutics targeting epigenetic regulators for these subtypes. Conversely, the conventional ductal PC subtype has emerged as a promising candidate for treatment with epigenetic modulators.

The lack of specific and sensitive early diagnostic options for pancreatic cancer (PC) results in patients being largely diagnosed with late-stage disease, thus inoperable and burdened with high mortality. Molecular spectroscopic methodologies, such as Raman or infrared spectroscopies, show promise in becoming a leader in screening for early-stage cancer diseases, including PC. However, should such technology be introduced, the identification of differentiating spectral features between various cancer types is required. This would not be possible without the precise extraction of spectra without the contamination by necrosis, inflammation, desmoplasia, or extracellular fluids such as mucous that surround tumor cells. Moreover, an efficient methodology for their interpretation has not been well defined. In this study, we compared different methods of spectral analysis to find the best for investigating the biomolecular composition of PC cells cytoplasm and nuclei separately. Sixteen PC tissue samples of main PC subtypes (ductal adenocarcinoma, intraductal papillary mucinous carcinoma, and ampulla of Vater carcinoma) were collected with Raman hyperspectral mapping, resulting in 191,355 Raman spectra and analyzed with comparative methodologies, specifically, hierarchical cluster analysis, non-negative matrix factorization, T-distributed stochastic neighbor embedding, principal components analysis (PCA), and convolutional neural networks (CNN). As a result, we propose an innovative approach to spectra classification by CNN, combined with PCA for molecular characterization. The CNN-based spectra classification achieved over 98% successful validation rate. Subsequent analyses of spectral features revealed differences among PC subtypes and between the cytoplasm and nuclei of their cells. Our study establishes an optimal methodology for cancer tissue spectral data classification and interpretation that allows precise and cognitive studies of cancer cells and their subcellular components, without mixing the results with cancer-surrounding tissue. As a proof of concept, we describe findings that add to the spectroscopic understanding of PC. Graphical Abstract

Even several thousands of DNA lesions are induced in one cell within one day. DNA damage may lead to mutations, formation of chromosomal aberrations, or cellular death. A particularly cytotoxic type of DNA damage is single- and double-strand breaks (SSBs and DSBs, respectively). In this work, we followed DNA conformational transitions induced by the disruption of DNA backbone. Conformational changes of chromatin in living cells were induced by a bleomycin (BLM), an anticancer drug, which generates SSBs and DSBs. Raman micro-spectroscopy enabled to observe chemical changes at the level of single cell and to collect hyperspectral images of molecular structure and composition with sub-micrometer resolution. We applied multivariate data analysis methods to extract key information from registered data, particularly to probe DNA conformational changes. Applied methodology enabled to track conformational transition from B-DNA to A-DNA upon cellular response to BLM treatment. Additionally, increased expression of proteins within the cell nucleus resulting from the activation of repair processes was demonstrated. The ongoing DNA repair process under the BLM action was also confirmed with confocal laser scanning fluorescent microscopy.

PurposeKnowledge about pancreatic cancer (PC) biology has been growing rapidly in recent decades. Nevertheless, the survival of PC patients has not greatly improved. The development of a novel methodology suitable for deep investigation of the nature of PC tumors is of great importance. Molecular imaging techniques, such as Fourier transform infrared (FTIR) spectroscopy and Raman hyperspectral mapping (RHM) combined with advanced multivariate data analysis, were useful in studying the biochemical composition of PC tissue.MethodsHere, we evaluated the potential of molecular imaging in differentiating three groups of PC tumors, which originate from different precursor lesions. Specifically, we comprehensively investigated adenocarcinomas (ACs): conventional ductal AC, intraductal papillary mucinous carcinoma, and ampulla of Vater AC. FTIR microspectroscopy and RHM maps of 24 PC tissue slides were obtained, and comprehensive advanced statistical analyses, such as hierarchical clustering and nonnegative matrix factorization, were performed on a total of 211,355 Raman spectra. Additionally, we employed deep learning technology for the same task of PC subtyping to enable automation. The so-called convolutional neural network (CNN) was trained to recognize spectra specific to each PC group and then employed to generate CNN-prediction-based tissue maps. To identify the DNA methylation spectral markers, we used differently methylated, isolated DNA and compared the observed spectral differences with the results obtained from cellular nuclei regions of PC tissues.ResultsThe results showed significant differences among cancer tissues of the studied PC groups. The main findings are the varying content of β-sheet-rich proteins within the PC cells and alterations in the relative DNA methylation level. Our CNN model efficiently differentiated PC groups with 94% accuracy. The usage of CNN in the classification task did not require Raman spectral data preprocessing and eliminated the need for extensive knowledge of statistical methodologies.ConclusionsMolecular spectroscopy combined with CNN technology is a powerful tool for PC detection and subtyping. The molecular fingerprint of DNA methylation and β-sheet cytoplasmic proteins established by our results is different for the main PC groups and allowed the subtyping of pancreatic tumors, which can improve patient management and increase their survival. Our observations are of key importance in understanding the variability of PC and allow translation of the methodology into clinical practice by utilizing liquid biopsy testing.

Celiac disease (CD) can only be treated by rigorous life-long gluten-free diet (GFD). The study included 102 mothers and their CD children treated with GFD for at least two years. Frequency and cause of diet failure in children treated at present (54 children) and 10 years ago (48 children) were compared. Dietary adherence was evaluated serologically (tTG), while diet management difficulties were examined by means of a questionnaire. The study shows that one-third of patients fail to follow GFD, more often 10 years ago than now (40% vs. 26%; p < 0.05), mainly children aged 13–18 (54% vs. 40% now; p < 0.05). Younger children (up to 12) are less likely to abandon the diet (27% vs. 8%; p < 0.05). In this age group non-intentional diet failure prevails, while teenagers interrupt their diet intentionally (45% vs. 33%; p = ns (small population of children in this groups)). Currently, the most common causes of teenage diet failure are the absence of symptoms after consuming a small amount of gluten and, even more often, troublesome diet administration. Previously, the absence of peer acceptance prevailed. With this study we found that: 1. In West Pomerania, every fourth CD child does not follow GFD. 2. For years, teenagers have failed to follow GFD due to the absence of symptoms after consuming small amounts of gluten. 3. The incidence of non-intentional failure to follow GFD has significantly decreased over years, which indicates better dietary care.

IgE-mediated wheat allergy is a gluten-related disorder. Wheat is one of the five most common food allergens in children. However, the natural history of IgE-mediated wheat allergy has seldom been described in the research literature. This study presents the current state of knowledge about the IgE-mediated wheat allergy in children.

Connecting pathways are essential for cultural and economic exchange. Commonly, historians investigate the role of routes for cultural development, whereas the environmental impacts of historical routes attract less attention. Here, we present a high-resolution reconstruction of the impact of the major trade route via Marchionis in the southern Baltic lowlands on landscape evolution since more than 800 years. We combine precisely dated annually laminated sediments from Lake Czechowskie alongside via Marchionis and pollen data at 5-year resolution together with historical data. The transformation from a quasi-natural to a cultural landscape occurred in three phases (1) an early phase until the mid-fourteenth century with slowly increasing human impact. (2) an intensification of environmental disturbance until (3) the mid-nineteenth century when via Marchionis became a modern traffic route with strong environmental impacts. Superimposed on the long-term development were repeated interruptions by short-term downturns related to societal crisis and political decisions.

Background Disruption in gut microbiota has been identified as a contributor to obesity-related inflammation and metabolic disorders. This study investigates the effects of preoperative probiotic supplementation on inflammation, endotoxemia, adipokines, and gastrointestinal peptides after bariatric surgery. Methods This randomized, double-blind, placebo-controlled clinical trial included patients undergoing laparoscopic sleeve gastrectomy (LSG) or one anastomosis gastric bypass (OAGB). Participants were randomized to receive a 12-week supplementation of either a probiotic mixture, Sanprobi Barrier, which contained nine strains of bacteria ( Bifidobacterium bifidum W23, Bifidobacterium lactis W51 and W52, Lactobacillus acidophilus W37, Levilactobacillus brevis W63, Lacticaseibacillus casei W56, Ligilactobacillus salivarius W24, Lactococcus lactis W19, and Lactococcus lactis W58), or a placebo before surgery. The key outcomes measured at baseline and 6 months postoperatively included serum lipopolysaccharide (LPS), cytokines (interleukin-6 – IL-6, interleukin-2 receptor—IL-2R, and C-reactive—CRP protein), adipokines (leptin, adiponectin, resistin), and gastrointestinal peptides (glucagon-like peptide-1 – GLP-1, ghrelin, and trefoil factor 2). Relative mRNA expression of ghrelin and trefoil family factor 2 in gastric tissues was also analyzed at baseline and on the day of the surgery. Results Out of the initial 110 participants, serum samples of 18 individuals in the probiotic group and 24 in the placebo group were analyzed. Both groups showed significant reductions in serum LPS levels six months after surgery; however, no significant differences were observed between the two groups. Adiponectin levels increased significantly in the placebo group (4.2 ± 2.3 vs. 2.2 ± 1.1 pg/mL; p <  0.001), while leptin levels decreased significantly in both groups without intergroup differences. IL-6 levels were significantly lower in the probiotic group compared to the placebo group at 6 months (2.2 ± 1.1 vs 4.2 ± 2.3 pg/mL; p  = 0.004). No significant differences were observed in the remaining cytokine levels between the groups. Gastrointestinal peptides showed no significant differences between the groups, although GLP-1 levels improved within both groups. No changes were observed in ghrelin and trefoil factor 2 expression at the mRNA level. Conclusions Preoperative probiotic therapy was associated with significantly lower IL-6 levels compared to placebo six months after surgery, suggesting a potential anti-inflammatory effect. However, since the between-group difference in IL-6 changes from baseline was not statistically significant, the observed effect should be interpreted with caution. Other measured markers were not significantly affected, though low statistical power may have limited detection of subtle effects. These findings suggest that while probiotics may reduce certain inflammatory responses, their efficacy can be overshadowed by bariatric surgery impact. The further studies on this subject are warranted. Trial registration The study was registered at ClinicalTrials.gov (NCT05407090).

Chronic kidney disease (CKD) is associated with an increased cardiovascular risk, including microvascular complications. Previous studies have shown alterations in the fatty acid profile in kidney transplant (KT) recipients, which included deficiencies in polyunsaturated fatty acids (PUFA). The goal of this study was to determine the associations between the fatty acid profile and microvascular parameters in KT patients. The fatty acids 22:4n-6 and 20:4n-3 negatively correlated with the wall-to-lumen ratio (WLR), with respective R-values being − 0.39 ( p  = 0.017) and − 0.405 ( p  = 0.013), suggesting their potential protective effect on microcirculation, despite their levels being decreased after KT. Additionally, 18:2n-6, a precursor of pro-inflammatory oxylipins, showed a positive correlation with the wall cross-sectional area (WCSA), which may indicate its negative impact on microvascular remodeling. Moreover, 22:5n-6 was associated with greater microcirculatory function reflected by the normoxia oscillatory index (NOI). Associations between microcirculation and branched-chain fatty acids (BCFA) were also observed. Iso C17 and iso C16 correlated positively with lumen diameter with R-values of 0.397 ( p  = 0.017) and 0.331 ( p  = 0.049), respectively, suggesting their beneficial effect on microcirculatory structure, while iso C15 was linked to the hyperemic response (HR) index. The study results indicate that certain circulating PUFA and BCFA are significantly associated with microvascular parameters, with most of them in a favorable (vasculoprotective) manner. Since these fatty acids may potentially improve microcirculation and their levels are reduced in KT patients, further studies are needed to explore their potential therapeutic role.