Search

RNA modifications, also termed epitranscriptomic marks, encompass chemical alterations to individual nucleotides, including processes such as methylation and editing. These marks contribute to a wide range of biological processes, many of which are related to host immune system defense. The functions of immune-related RNA modifications can be categorized into three main groups: regulation of immunogenic RNAs, control of genes involved in innate immune response, and facilitation of adaptive immunity. Here, we provide an overview of recent research findings that elucidate the contributions of RNA modifications to each of these processes. We also discuss relevant methods for genome-wide identification of RNA modifications and their immunogenic substrates. Finally, we highlight recent advances in cancer immunotherapies that aim to reduce cancer cell viability by targeting the enzymes responsible for RNA modifications. Our presentation of these dynamic research avenues sets the stage for future investigations in this field.

Abstract High rates of cardiometabolic disease and poor physical health outcomes contribute to significant premature mortality in people living with severe mental illness (PLWSMI). Lifestyle interventions such as exercise are known to improve both physical and mental health outcomes, however the best way to deliver exercise programs for PLWSMI remains a challenge. This paper uses a pragmatic program evaluation of a co-delivered low-cost community-based exercise program implemented over a 6-month period. Of 46 referrals in the first half of 2023 to the SLHD Gym and Swim program, 13 gave consent to participate in standardised measures and qualitative interviews. Findings revealed an increase in average hours of sport/exercise, improvements in confidence to exercise independently and within group settings, as well as achievement of individualised goals. The success of the program was in part due to the co-facilitation between peer support workers and exercise physiologists, community connection and the established partnership between the public health service and the local government council. Results offer evidence to adopt and implement accessible and low-cost exercise opportunities in the community external to health services to address barriers of attendance for PLWSMI.

Mental health challenges are on the rise among today's youth. Recent reports have noted an acute and significant need for school-based mental health education and supportive interventions for children and adolescents. Among these approaches, a growing focus has centered on improving students' mental health literacy (MHL) as a foundational component in addressing overall mental health needs. While schools offer an ideal venue for access and implementation, there exist a variety of limitations to integrating MHL content, particularly within the middle school classroom. In this manuscript, we offer recommendations for educators, school social support workers, and administrators who are interested in teaming together to develop and embed a literature-based MHL curriculum into the middle school English Language Arts (ELA) classroom. Our suggestions offer a framework for planning, developing, and implementing such a curriculum within the confines of current school structures and processes while maintaining the teacher's role as educator.

Drama therapy incorporates play, imaginary engagement, embodiment, and perspective taking to promote interpersonal skills and affective functioning. Existing school-based drama therapy (SBDT) research has demonstrated utility with select populations; however, much of the SBDT literature has featured disparate findings. Absent from the current literature is a thorough synthesis of the benefits of SBDT for socio-emotional development in early childhood, an age cohort that may be well suited for drama therapy due to the method's theoretical and practical focus on action, symbolism, and play. A scoping review was conducted to answer the research question: "What is the use and potential of SBDT to enhance socio-emotional skills in early childhood?" Following a thorough database and manual search, 406 articles were identified and, after screening, 16 articles met the inclusion criteria. Based on the results, practice recommendations include the use of metaphor, distance, and life-drama connection to enhance socio-emotional skills, using dramatic play as a tool to address adverse experiences, and applying SBDT to support specific clinical populations. Policy recommendations include the use of SBDT within a public health trauma approach and the need for ecological integration of SBDT into schools. Research recommendations include the need for a broad-level articulation of a scaffolded SBDT research agenda in schools focused on socio-emotional skills and recommendations specific to methodological and reporting rigor.

Abstract Seminal plasma (SP) is the main vector of C. trachomatis (CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimental in vitro model to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.

This work aims to develop fast T1 mapping methods for preclinical and clinical scanners based on subspace-constrained reconstructions. Two sequences are explored for rapid T1 characterizations: 1) Interleaved spatiotemporal encoding incorporating variable repetition times. 2) Inversion recovery gradient echo with random sampling of the phase-encoding (PE) dimension. For both sequences, the subspace reconstruction of the signal recovery was applied, to jointly reconstruct the down-sampled images while characterizing the T1 relaxation. In vivo scans on human brains and abdomens confirmed the efficiency of the proposed methods, including compatibility with breath-holding. In addition, Scans on animals with abdominal tumors and dynamic contrast-enhanced T1 mapping on kidneys support the applicability of the proposed methods also in preclinical settings.

In asexual populations that don’t undergo recombination, such as cancer, deleterious mutations are expected to accrue readily due to genome-wide linkage between mutations. Despite this mutational load of often thousands of deleterious mutations, many tumors thrive. How tumors survive the damaging consequences of this mutational load is not well understood. Here, we investigate the functional consequences of mutational load in 10,295 human tumors by quantifying their phenotypic response through changes in gene expression. Using a generalized linear mixed model (GLMM), we find that high mutational load tumors up-regulate proteostasis machinery related to the mitigation and prevention of protein misfolding. We replicate these expression responses in cancer cell lines and show that the viability in high mutational load cancer cells is strongly dependent on complexes that degrade and refold proteins. This indicates that the upregulation of proteostasis machinery is causally important for high mutational burden tumors and uncovers new therapeutic vulnerabilities.

The dynamic structures of microbial communities emerge from the complex network of interactions between their constituent microorganisms. Quantitative measurements of these interactions are important for understanding and engineering ecosystem structure. Here, we present the development and application of the BioMe plate, a redesigned microplate device in which pairs of wells are separated by porous membranes. BioMe facilitates the measurement of dynamic microbial interactions and integrates easily with standard laboratory equipment. We first applied BioMe to recapitulate recently characterized, natural symbiotic interactions between bacteria isolated from the Drosophila melanogaster gut microbiome. Specifically, the BioMe plate allowed us to observe the benefit provided by two Lactobacillus strains to an Acetobacter strain. We next explored the use of BioMe to gain quantitative insight into the engineered obligate syntrophic interaction between a pair of Escherichia coli amino acid auxotrophs. We integrated experimental observations with a mechanistic computational model to quantify key parameters associated with this syntrophic interaction, including metabolite secretion and diffusion rates. This model also allowed us to explain the slow growth observed for auxotrophs growing in adjacent wells by demonstrating that, under the relevant range of parameters, local exchange between auxotrophs is essential for efficient growth. The BioMe plate provides a scalable and flexible approach for the study of dynamic microbial interactions. IMPORTANCE Microbial communities participate in many essential processes from biogeochemical cycles to the maintenance of human health. The structure and functions of these communities are dynamic properties that depend on poorly understood interactions among different species. Unraveling these interactions is therefore a crucial step toward understanding natural microbiota and engineering artificial ones. Microbial interactions have been difficult to measure directly, largely due to limitations of existing methods to disentangle the contribution of different organisms in mixed cocultures. To overcome these limitations, we developed the BioMe plate, a custom microplate-based device that enables direct measurement of microbial interactions, by detecting the abundance of segregated populations of microbes that can exchange small molecules through a membrane. We demonstrated the possible application of the BioMe plate for studying both natural and artificial consortia. BioMe is a scalable and accessible platform that can be used to broadly characterize microbial interactions mediated by diffusible molecules.

Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

Abstract Background and Aims The diagnosis of acute kidney injury (AKI) is of importance among patients with ST segment elevation (STEMI) undergoing primary coronary intervention (PCI). It is often delayed given the need in serial measurements of creatinine or other serum markers. Neutrophil gelatinase‐associated lipocalin (NGAL) is a proven marker for AKI, although its role as an early predictor in this setting was scarcely addressed before and was the aim of our study. Methods Prospective observational study including 133 patients with STEMI treated with PCI. Plasma NGAL was drawn immediately before PCI (NGAL‐0) and 24 h after (NGAL‐24). Similar analysis of C‐reactive protein (CRP) was performed for additional comparison. Results Mean age was 62 ± 13 years, 78% were men, and 20 (15%) developed AKI after admission. Patients with AKI after admission demonstrated higher levels of NGAL‐0 (164 vs. 95 ng/mL; p

Abstract Proper cellular proteostasis, essential for viability, requires a network of chaperones and cochaperones. ATP-dependent chaperonin TRiC/CCT partners with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate folding of essential eukaryotic proteins. Using cryoEM and biochemical analyses, we determine the ATP-driven cycle of TRiC-PFD-PhLP2A interaction. PhLP2A binds to open apo-TRiC through polyvalent domain-specific contacts with its chamber’s equatorial and apical regions. PhLP2A N-terminal H3-domain binding to subunits CCT3/4 apical domains displace PFD from TRiC. ATP-induced TRiC closure rearranges the contacts of PhLP2A domains within the closed chamber. In the presence of substrate, actin and PhLP2A segregate into opposing chambers, each binding to positively charged inner surface residues from CCT1/3/6/8. Notably, actin induces a conformational change in PhLP2A, causing its N-terminal helices to extend across the inter-ring interface to directly contact a hydrophobic groove in actin. Our findings reveal an ATP-driven PhLP2A structural rearrangement cycle within the TRiC chamber to facilitate folding.