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Cloud computing is a new way of delivering computing resources and services. Many managers and experts believe that it can improve health care services, benefit health care research, and change the face of health information technology. However, as with any innovation, cloud computing should be rigorously evaluated before its widespread adoption. This paper discusses the concept and its current place in health care, and uses 4 aspects (management, technology, security, and legal) to evaluate the opportunities and challenges of this computing model. Strategic planning that could be used by a health organization to determine its direction, strategy, and resource allocation when it has decided to migrate from traditional to cloud-based health services is also discussed.

The ORC1 BAH domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin syndrome. Histone methylation linked to DNA replication ORC1 is a subunit of the replication-licensing machinery that associates with replication origins, and mutations in the ORC1 BAH domain have been associated with a dwarfism syndrome. Here, the ORC1 BAH domain is shown to comprise a module that recognizes a histone modification associated with replication origins. Insight into the molecular basis of the interaction is provided by a crystal structure. The interaction between ORC1 BAH domain and the histone modification is required for loading of ORC onto chromatin, and is also required to prevent dwarfism in a zebrafish model of the disease. The recognition of distinctly modified histones by specialized ‘effector’ proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes 1 . Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1—a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing 2 —contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier–Gorlin syndrome (MGS) 3 , 4 , a form of primordial dwarfism 5 , and ORC1 depletion in zebrafish results in an MGS-like phenotype 4 . We find that wild-type human ORC1, but not ORC1–H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development. Chromatin undergoes extensive reprogramming during immune cell differentiation. Here Kuo and colleagues uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Cells, the basic units of life, have striking differences at transcriptomic, proteomic and epigenomic levels across tissues, organs, organ systems and organisms. The coordination of individual immune cells is essential for the generation of effective immune responses to pathogens while immune tolerance is maintained to protect the host. In rheumatic diseases, when immune responses are dysregulated, pathologically important cells might represent only a small fraction of the immune system. Interrogation of the contributions of individual immune cells to pathogenesis and disease progression should therefore reveal important insights into the complicated aetiology of rheumatic diseases. Technological advances are enabling the high-dimensional dissection of single cells at multiple omics levels, which could facilitate the identification of dysregulated molecular mechanisms in patients with rheumatic diseases and the discovery of new therapeutic targets and biomarkers. The single-cell technologies that have been developed over the past decade and the experimental platforms that enable multi-omics integrative analyses have already made inroads into immunology-related fields of study and have potential for use in rheumatology. Layers of omics data derived from single cells are likely to fundamentally change our understanding of the molecular pathways that underpin the pathogenesis of rheumatic diseases.Single-cell sequencing technologies enable transcriptomic, epigenomic and proteomic analysis of rare or heterogeneous populations of cells. In this Review, Kuo and colleagues discuss current and future uses of single-cell sequencing technologies for rheumatology research.

Knowledge of protein domains that function as the biological effectors for diverse post-translational modifications of histones is critical for understanding how nuclear and epigenetic programs are established. Indeed, mutations of chromatin effector domains found within several proteins are associated with multiple human pathologies, including cancer and immunodeficiency syndromes. To date, relatively few effector domains have been identified in comparison to the number of modifications present on histone and non-histone proteins. Here we describe the generation and application of human modified peptide microarrays as a platform for high-throughput discovery of chromatin effectors and for epitope-specificity analysis of antibodies commonly utilized in chromatin research. Screening with a library containing a majority of the Royal Family domains present in the human proteome led to the discovery of TDRD7, JMJ2C, and MPP8 as three new modified histone-binding proteins. Thus, we propose that peptide microarray methodologies are a powerful new tool for elucidating molecular interactions at chromatin.

Binding of the transcription factor NF-κB subunit RelA activates proinflammatory gene expression. Gozani and colleagues show that basal expression of RelA target genes is suppressed by methylation of RelA by SETD6, which triggers repressive histone methylation by GLP. Signaling via the methylation of lysine residues in proteins has been linked to diverse biological and disease processes, yet the catalytic activity and substrate specificity of many human protein lysine methyltransferases (PKMTs) are unknown. We screened over 40 candidate PKMTs and identified SETD6 as a methyltransferase that monomethylated chromatin-associated transcription factor NF-κB subunit RelA at Lys310 (RelAK310me1). SETD6-mediated methylation rendered RelA inert and attenuated RelA-driven transcriptional programs, including inflammatory responses in primary immune cells. RelAK310me1 was recognized by the ankryin repeat of the histone methyltransferase GLP, which under basal conditions promoted a repressed chromatin state at RelA target genes through GLP-mediated methylation of histone H3 Lys9 (H3K9). NF-κB-activation–linked phosphorylation of RelA at Ser311 by protein kinase C-ζ (PKC-ζ) blocked the binding of GLP to RelAK310me1 and relieved repression of the target gene. Our findings establish a previously uncharacterized mechanism by which chromatin signaling regulates inflammation programs.

Electronic health records (EHRs) play an essential role in modern health care, enabling data sharing and improving patient safety; however, even though vendors must adhere to International Organization for Standardization-related usability standards for EHR certification, persistent usability issues continue to undermine efficiency, contribute to clinician burden, and increase the risk of preventable errors. This scoping review synthesizes existing research on EHR adoption and usability, emphasizing theoretical models, measurement approaches, factors, and analytic methods used to assess or predict usability. We identify gaps and opportunities for integrating predictive analytics and artificial intelligence (AI) to advance research and improve the usability of EHRs. Following Joanna Briggs Institute and PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines, we systematically searched MEDLINE, Web of Science, IEEE Xplore, and Scopus library databases for studies published between January 1, 2009, and April 9, 2025. Inclusion criteria focused on empirical research using predictive methods or models related to EHR usability. Data were charted and synthesized thematically. Of the 2323 screened papers, 47 studies met inclusion criteria. Most research examined or predicted EHR adoption (not usability) using dominant frameworks, such as the technology acceptance model, unified theory of acceptance and use of technology, and the information system success model, which comprised usability. Factors related to usability-particularly perceived usefulness, perceived ease of use, effort expectancy, and facilitating conditions via the EHR adoption models-appeared frequently. Regression-based methods and structural equation modeling were the most common analytic techniques. No studies applied predictive modeling or AI to predict EHR usability. The focus of this study on the prediction of EHR usability and adoption for the past 15 years is distinctive in the literature. It extends prior usability reviews (mostly focusing on adoption, not prediction of usability). Predictive modeling for EHR usability remains underdeveloped throughout 2009 to 2025. Dominant frameworks in the EHR literature continue to prioritize predicting adoption over operational usability. These models rely heavily on self-reported, cross-sectional measures captured at a single postimplementation time point, embedding systematic bias and obscuring longitudinal usability dynamics. Despite the application of increasingly sophisticated predictive techniques-primarily variants of regression and structural equation modeling-usability has remained analytically subordinate to adoption and acceptance constructs for more than 15 years. As a result, widely used models, such as the technology acceptance model and unified theory of acceptance and use of technology, position usability merely as an antecedent to intention or use, rather than as an independent, system-level property that can be empirically measured, modeled, and predicted. Therefore, there is substantial opportunity to integrate predictive analytics, AI, and longitudinal usability measures to build dynamic models.

Recombination activating gene (RAG) 1 and RAG2 together catalyze V(D)J gene rearrangement in lymphocytes as the first step in the assembly and maturation of antigen receptors. RAG2 contains a plant homeodomain (PHD) near its C terminus (RAG2-PHD) that recognizes histone H3 methylated at lysine 4 (H3K4me) and influences V(D)J recombination. We report here crystal structures of RAG2-PHD alone and complexed with five modified H3 peptides. Two aspects of RAG2-PHD are unique. First, in the absence of the modified peptide, a peptide N-terminal to RAG2-PHD occupies the substrate-binding site, which may reflect an autoregulatory mechanism. Second, in contrast to other H3K4me3-binding PHD domains, RAG2-PHD substitutes a carboxylate that interacts with arginine 2 (R2) with a Tyr, resulting in binding to H3K4me3 that is enhanced rather than inhibited by dimethylation of R2. Five residues involved in histone H3 recognition were found mutated in severe combined immunodeficiency (SCID) patients. Disruption of the RAG2-PHD structure appears to lead to the absence of T and B lymphocytes, whereas failure to bind H3K4me3 is linked to Omenn Syndrome. This work provides a molecular basis for chromatin-dependent gene recombination and presents a single protein domain that simultaneously recognizes two distinct histone modifications, revealing added complexity in the read-out of combinatorial histone modifications.

Aire induces ectopic expression of peripheral tissue antigens (PTAs) in thymic medullary epithelial cells, which promotes immunological tolerance. Beginning with a broad screen of histone peptides, we demonstrate that the mechanism by which this single factor controls the transcription of thousands of genes involves recognition of the amino-terminal tail of histone H3, but not of other histones, by one of Aire's plant homeodomain (PHD) fingers. Certain posttranslational modifications of H3 tails, notably dimethylation or trimethylation at H3K4, abrogated binding by Aire, whereas others were tolerated. Similar PHD finger-H3 tail-binding properties were recently reported for BRAF-histone deacetylase complex 80 and DNA methyltransferase 3L; sequence alignment, molecular modeling, and biochemical analyses showed these factors and Aire to have structure-function relationships in common. In addition, certain PHD1 mutations underlying the polyendocrine disorder autoimmune polyendocrinopathy-candidiases-ectodermaldystrophy compromised Aire recognition of H3. In vitro binding assays demonstrated direct physical interaction between Aire and nucleosomes, which was in part buttressed by its affinity to DNA. In vivo Aire interactions with chromosomal regions depleted of H3K4me3 were dependent on its H3 tail-binding activity, and this binding was necessary but not sufficient for the up-regulation of genes encoding PTAs. Thus, Aire's activity as a histone-binding module mediates the thymic display of PTAs that promotes self-tolerance and prevents organ-specific autoimmunity.

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8-/- mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8+/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8-/- macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.