Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity

The interrelations of radiologic findings and mechanical ventilation in community acquired pneumonia patients admitted to the intensive care unit: a multicentre retrospective study

BACKGROUND: We evaluated patients admitted to the intensive care units with the diagnosis of community acquired pneumonia (CAP) regarding initial radiographic findings. METHODS: A multicenter retrospective study was held. Chest x ray (CXR) and computerized tomography (CT) findings and also their associations with the need of ventilator support were evaluated. RESULTS: A total of 388 patients were enrolled. Consolidation was the main finding on CXR (89%) and CT (80%) examinations. Of all, 45% had multi-lobar involvement. Bilateral involvement was found in 40% and 44% on CXR and CT respectively. Abscesses and cavitations were rarely found. The highest correlation between CT and CXR findings was observed for interstitial involvement. More than 80% of patients needed ventilator support. Noninvasive mechanical ventilation (NIV) requirement was seen to be more common in those with multi-lobar involvement on CXR as 2.4-fold and consolidation on CT as 47-fold compared with those who do not have these findings. Invasive mechanical ventilation (IMV) need increased 8-fold in patients with multi-lobar involvement on CT. CONCLUSION: CXR and CT findings correlate up to a limit in terms of interstitial involvement but not in high percentages in other findings. CAP patients who are admitted to the ICU are severe cases frequently requiring ventilator support. Initial CT and CXR findings may indicate the need for ventilator support, but the assumed ongoing real practice is important and the value of radiologic evaluation beyond clinical findings to predict the mechanical ventilation need is subject for further evaluation with large patient series

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity

EWS-FLI1 Utilizes Divergent Chromatin Remodeling Mechanisms to Directly Activate or Repress Enhancer Elements in Ewing Sarcoma

SummaryThe aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation

Privacy Preserving Data Sharing and Processing

Cloud computing has become a ubiquitous mechanism to store, share and process data. To preserve data privacy, a data owner may encrypt the data before uploading it to the cloud. The encryption, however, also needs to support efficient data sharing and processing to preserve the utility of the data. In this dissertation, we investigate secure and efficient data sharing and processing in the cloud. The first part of the dissertation focuses on secure and efficient encrypted keyword search for multi-user data sharing. Specifically, a data owner outsources a set of encrypted files to an untrusted cloud server, shares it with a set of users, and a user is allowed to search keywords in a subset of the files that he is authorized to access. We propose a secure and efficient Multi-user Encrypted Keyword Search (SEMEKS) scheme. In this scheme, (a) each user has a constant size secret key, (b) each user generates a constant size trapdoor for a keyword without getting any help from any party (e.g., data owner), independent of the number of the file that he is authorized to search, and (c) for the keyword ciphertexts of a file, the network bandwidth usage (from the data owner to the server) and storage overhead at the server do not depend on the number of users that are authorized to access the file. We show that our scheme has data privacy and trapdoor privacy. In the second part of the dissertation, we propose a new distributed parameter generation protocol that eliminates the need of a single trust party and works for a class of cryptographic primitives. In particular, it can be used to extend our SEMEKS scheme described earlier. It also has broad applications in distributed multi-party oriented cryptographic schemes, including broadcast encryption, revocation systems and identity-based encryption. Specifically, building upon previous distributed key generation protocols for discrete logarithms, we provide two new building blocks that one can use sequentially to derive distributed parameter generation protocols for a class of problems in the bilinear groups setting, most notably the n-Bilinear Diffie Hellman Exponentiation problem. The last part of the dissertation focuses on secure and efficient set intersection over encrypted data sets in a cloud setting. Basically, assume two users, Alice and Bob, outsource their encrypted datasets to a cloud server, and then want to perform an intersection operation over their encrypted data sets. Our construction, Secure Verifiable Delegated Set Intersection (SEVDSI), is efficient: the amount of communication between a user and the cloud server is linear in the set intersection cardinality, while the amount of computation (performed by the cloud server) is linear in the user’s dataset. In addition, SEVDSI provides verifiability (users can verify if the cloud server honestly computes the set intersection operation), forward secrecy (a user can add new data items to his current dataset efficiently and the cloud server is not able to figure out if the new data item satisfies set intersection protocol that was happened in the past), and multi-user set intersection (a user can do set intersection protocol many times with different users). To the best of our knowledge, SEVDSI is the first scheme that has all the above properties

Time‐specific encrypted range query with minimum leakage disclosure

Abstract A time‐specific encrypted range query scheme that has the following properties is proposed. (1) The proposed scheme has trapdoor privacy and data privacy so that a semi‐honest cloud is not able to get any useful information from given ciphertexts and given tokens that are used for searching ranges. (2) Unlike most of the other studies which report that the cloud server stores single encrypted keyword/element in the database, in our solution, the cloud server stores encrypted multi‐keywords/ranges in the database. Therefore, the semi‐honest cloud compares ciphertexts to tokens as ranges based on a predefined threshold ϕ value. This approach decreases the cloud search time since the cloud compares ranges to ranges (multi‐keywords with multi‐keywords) not points to points (not a keyword with a keyword). Thus, the proposed scheme is efficient based on searching ranges on ciphertexts. (3) Moreover, the communication cost between users and the cloud is decreased from O(n) to O(log  n), where n is the size of a range. Users send logarithmic size information to the cloud server instead of sending linear size information