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Abstract Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn’s disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC.

Abstract Breast cancer is one of the leading causes of death in females, mainly because of metastasis. Oncometabolites, produced via metabolic reprogramming, can influence metastatic signaling cascades. Accordingly, and based on our previous results, we propose that metabolites from highly metastatic breast cancer cells behave differently from less-metastatic cells and may play a significant role in metastasis. For instance, we aim to identify these metabolites and their role in breast cancer metastasis. Less metastatic cells (MCF-7) were treated with metabolites secreted from highly metastatic cells (MDA-MB-231) and the gene expression of three epithelial-to-mesenchymal transition (EMT) markers including E-cadherin, N-cadherin and vimentin were examined. Some metabolites secreted from MDA-MB-231 cells significantly induced EMT activity. Specifically, hypoxanthine demonstrated a significant EMT effect and increased the migration and invasion effects of MCF-7 cells through a hypoxia-associated mechanism. Hypoxanthine exhibited pro-angiogenic effects via increasing the VEGF and PDGF gene expression and affected lipid metabolism by increasing the gene expression of PCSK-9. Notably, knockdown of purine nucleoside phosphorylase, a gene encoding for an important enzyme in the biosynthesis of hypoxanthine, and inhibition of hypoxanthine uptake caused a significant decrease in hypoxanthine-associated EMT effects. Collectively for the first time, hypoxanthine was identified as a novel metastasis-associated metabolite in breast cancer cells and represents a promising target for diagnosis and therapy.

The use of 12-bit levels of grayscale in medical image representation allows for more precise image analysis and diagnosis, and encrypting such images is essential for protecting patient privacy and security. Existing 8-bit image encryption schemes become inefficient when applied to 12-bit images. In this paper, we design a cryptographically strong encryption scheme to improve the efficiency of encrypting 12-bit medical images. The core of the proposed scheme is a key-dependent $12\times 12$ S-box, which plays a crucial role in enhancing the security and efficiency of the encryption scheme. Most notably, test results show that $12\times 12$ S-boxes offer significantly stronger confusion and key-sensitivity than their $8\times 8$ counterparts. This finding enables the proposed $12\times 12$ S-box-based scheme to process 12-bit images 3.3 times faster than an $8\times 8$ S-box while passing all security tests. Experimental results show that the proposed scheme can encrypt 12-bit images at speeds up to 300MB/s. Moreover, the proposed scheme has also been shown to efficiently handle 8-bit images. Comparative results highlight the security and efficiency advantages of the proposed scheme over existing medical image encryption schemes.

Introduction: Mitochondria are maternally inherited cell organelles with their own genome, and perform various functions in eukaryotic cells such as energy production and cellular homeostasis. Due to their inheritance and manifold biological roles in health and disease, mitochondrial genetics serves a dual purpose of tracing the history as well as disease susceptibility of human populations across the globe. This work requires a comprehensive catalogue of commonly observed genetic variations in the mitochondrial DNAs for all regions throughout the world. So far, however, certain regions, such as North and East Africa have been understudied. Objectives: To address this shortcoming, we have created the most comprehensive quality-controlled North and East African mitochondrial data set to date and use it for characterizing mitochondrial genetic variation in this region. Methods: We compiled 11 published cohorts with novel data for mitochondrial genomes from 159 Sudanese individuals. We combined these 641 mitochondrial sequences with sequences from the 1000 Genomes (n = 2504) and the Human Genome Diversity Project (n = 828) and used the tool haplocheck for extensive quality control and detection of in-sample contamination, as well as Nanopore long read sequencing for haplogroup validation of 18 samples. Results: Using a subset of high-coverage mitochondrial sequences, we predict 15 potentially novel haplogroups in North and East African subjects and observe likely phylogenetic deviations from the established PhyloTree reference for haplogroups L0a1 and L2a1. Conclusion: Our findings demonstrate common hitherto unexplored variants in mitochondrial genomes of North and East Africa that lead to novel phylogenetic relationships between haplogroups present in these regions. These observations call for further in-depth population genetic studies in that region to enable the prospective use of mitochondrial genetic variation for precision medicine.

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.

Detlef Zillikens, MD, director and chair of the Department of Dermatology at the University of Lübeck, Lübeck, Germany, died in September 2022, aged only 64. He dedicated his professional life to autoimmune blistering diseases (AIBDs) and built his department into one of the world’s leading centers for these diseases. Herein, his professional life and the impact on the field of AIBDs and the research landscape at the University of Lübeck are addressed. With his warm, integrative, open-minded, ever-optimistic attitude, he was a highly reliable colleague, mentor, and friend to many in the field including each of the authors. Combined with his in-depth knowledge of dermatology, interest in many fields of life science, and hard work, Detlef Zillikens initiated the founding of two independent research institutes, the Lübeck Institute of Experimental Dermatology and the Institute and Comprehensive Center for Inflammation Medicine. He was also instrumental in establishing the Center for Research on Inflammation of the Skin, where in a new research building, over 140 scientists pursue research questions related to skin inflammation. By inviting numerous researchers and clinicians to his department and hosting two large international meetings, he brought the field of AIBDs much closer together and inspired multiple national and international research initiatives. His ideas will live on and grow in many of his colleagues and mentees.

Introduction: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. Objectives: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. Methods: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. Results: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. Conclusion: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting.

Background and Aims: Extensive surgical retraction combined with general anesthesia increase alveolar collapse. The primary aim of our study was to investigate the effect of alveolar recruitment maneuver (ARM) on arterial oxygenation tension (PaO2). The secondary aim was to observe its effect on hemodynamics parameters in hepatic patients during liver resection, to investigate its impact on blood loss, postoperative pulmonary complications (PPC), remnant liver function tests, and on the outcome. Material and Methods: Adult patients scheduled for liver resection were randomized into two groups: ARM (n = 21) and control (C) (n = 21). Stepwise ARM was initiated after intubation and was repeated post-retraction. Pressure-control ventilation mode was adjusted to deliver a tidal volume (Vt) of 6 mL/kg and an inspiratory-to-expiratory time (I:E) ratio of 1:2 with an optimal positive end-expiratory pressure (PEEP) for the ARM group. In the C group, a fixed PEEP (5 cmH2O) was applied. Invasive intra-arterial blood pressure (IBP), central venous pressure (CVP), electrical cardiometry (EC), alanine transaminase (ALT, U/L), and aspartate aminotransferase (AST, U/L) blood levels were monitored. Results: ARM increased PEEP, dynamic compliances, and arterial oxygenation, but reduced ventilator driving pressure compared to group C (P < 0.01). IBP, cardiac output (CO), and stroke volume variation were not affected by the higher PEEP in the ARM group (P > 0.05) but the CVP increased significantly (P = 0.001). Blood loss was not different between the ARM and C groups (1700 (1150–2000) mL vs 1110 (900–2400) mL, respectively and P = 0.57). ARM reduced postoperative oxygen desaturation; however, it did not affect the increase in remnant liver enzymes and was comparable to group C (ALT, P = 0.54, AST, P = 0.41). Conclusions: ARM improved intraoperative lung mechanics and reduced oxygen desaturation episodes in recovery, but not PPC or ICU stay. ARM was tolerated with minimal cardiac and systemic hemodynamic effects.