Tisch Hospital

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are strongly involved in its pathogenesis. We derived cerebral and spinal cord organoids from induced pluripotent stem cells (iPSC) from healthy controls as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients to investigate and compare oligodendrocyte differentiation and myelination capacity. In MS organoids, particularly in PPMS, we observed a decrease in p21 expression associated with a dysregulation of PAK1 and E2F1 expression. In parallel, a decrease in oligodendrocyte maturation was detected in long-term cultured cerebral and spinal cord organoids, especially in PPMS, leading to a reduced myelination capacity. Disruption of astrocyte and neuronal populations was also observed. Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter glial and neuronal cell populations and may contribute to the disease pathogenesis by reducing the capacity for myelin repair.

Numerous studies show that individuals’ satisfaction with their leisure relates to other aspects of their lives such as perceived quality of life, life satisfaction, subjective wellbeing, and self-rated health. However, the factors that lead to differences in leisure satisfaction are less well known, especially those involving culture. The purpose of this study is to determine which, among several variables common to samples from locations in Mainland China, Taiwan, and Brazil, best predict leisure satisfaction. An individual participant data meta-analysis indicates that age, education, income, and marital status are significant predictors. Frequency of participation in active leisure pursuits and the perceived importance of interpersonal leisure constraints significantly predict leisure satisfaction, as well. Finally, as our primary interest is in the predictive value of culture-related variables, we examine cultural competence, knowledge of the degree to which individuals know the cultural model of the importance of various leisure activities to a good lifestyle, and cultural consonance, the frequency in which individuals claim to participate in those activities, as predictors. Results indicate that cultural consonance with respect to activities agreed upon as high in importance to a good lifestyle is a robust predictor of leisure satisfaction but that cultural competence is not.

Abstract Background Parenteral COVID-19 vaccines induce strong systemic immunity, but they do not typically trigger pronounced respiratory immunity. In this context, mucosally applied vaccines might help to induce local immune responses for early viral clearance and reduced viral transmission. Methods In this investigator-initiated, open-label single-dose phase I trial, we analyzed the immunogenicity and safety of the vaccine candidate MVA-SARS-2-ST administered as an inhalation boost in COVID-19-immunized adults (n=23). MVA-SARS-2-ST represents a replication-deficient vector vaccine candidate built on the recombinant Modified Vaccinia virus Ankara (MVA) platform and expresses a prefusion-stabilized version of the full-length spike glycoprotein of SARS-CoV-2. Results While there was no increase in spike-specific antibodies in the blood, the inhalation of 10 7 infectious units (IU) MVA-SARS-2-ST led to an increase in IFN-γ release after re-stimulation of whole blood with spike peptides. This enhanced IFN-γ release peaked at day 7 and remained detectable for at least 140 days after vaccination. Notably, selectively individuals with a history of COVID-19 (nucleocapsid protein (NCP)-seropositive study participants), but not individuals without a history of COVID-19 (NCP-seronegative study participants), showed a trend towards increased spike-specific IgA in the lung after inhalation of 10 7 IU MVA-SARS-2-ST. In contrast, inhaled application of MVA-SARS-2-ST robustly induced spike-specific CD4+ and CD8+ T cell responses in the lung in both NCP-seronegative and NCP-seropositive individuals. Conclusions Collectively, our study demonstrated that a single booster inhalation of 10 7 IU MVA-SARS-2-ST did not have a relevant impact on the humoral immune response, but induced specific T cell responses in blood and lung.

The rise of Artificial Intelligence (AI) in scholarly publishing is rapidly reshaping the peer review process.Once limited to tasks like plagiarism checks and manuscript triage, AI tools now assist in reviewer selection, ethical screening, and even pre-evaluation.While these innovations offer unmatched efficiency and scalability, particularly beneficial for under-resourced journals, they also pose serious concerns regarding transparency, editorial independence, and bias.This perspective explores the evolving role of AI in peer review, highlighting its dual potential as both a powerful tool and a source of ethical risk.Drawing on recent studies and global publishing practices, we argue that AI should enhance, not replace, human judgment in peer evaluation.The article proposes practical best practices for responsible integration, emphasizing transparency, bias mitigation, and global accessibility.It concludes with a call for balanced and inclusive approaches that protect editorial integrity while leveraging the benefits of AI.

Monocytes are recruited to tumors and undergo transcriptional reprogramming resulting in tumor-promoting functions. Epigenomic features, such as post-translational modification of histones and chromatin accessibility, are key determinants of transcription factor binding and thereby play an important role in controlling transcriptional responses to the tissue environment. It remains unknown whether systemic tumor-associated signals could alter the epigenomic landscape of peripheral monocytes before they reach the tumor, thus shaping their subsequent response to the tumor microenvironment. We used a combination of genome-wide assays for chromatin accessibility and multiple histone modifications (H3K4me1, H3K4me3, H3K27ac) in a mouse tumor model to investigate changes in the epigenomic landscape of peripheral monocytes. We then integrated these epigenomic data with transcriptomic data to link altered regulatory elements to gene expression changes in monocytes occurring in the periphery or during tumor infiltration. We found that tumor-induced systemic inflammation was associated with transcriptional and epigenomic preconditioning of peripheral monocytes. The distal tumor caused extensive remodeling of both H3K4me3+ promoters and H3K4me1+ enhancers. Specifically, this involved the repression of interferon-responsive regulatory elements as well as the establishment of enhancers harboring binding motifs for transcription factor families downstream of pro-inflammatory signaling, such as C/EBP, AP-1, and STAT. Reprogrammed enhancers in peripheral monocytes were linked to sustained gene expression changes that persisted after tumor infiltration. In addition, key pro-tumor genes upregulated in tumor-infiltrating monocytes showed epigenetic priming already in the circulation. These results suggest that cancer-associated remodeling of the epigenomic landscape in peripheral monocytes can shape the gene expression programs they acquire in the tumor, highlighting the role of the epigenome in redirecting monocyte function to support cancer progression.