Architecture Domain Research Articles

An Approach of Defining Domain Constraints for Domain-Specific Modeling Language

Many Domain-Specific Modeling Languages (DSML) cannot formally define their semantics, leading to difficulties in identifying user-defined domain constraints. In this study, we propose a user-defined mechanism of domain constraints based on the formalization of structural semantics of DSML. First, we formally define concepts and decision methods of consistency and validity of domain constraints. Subsequently, we establish concepts and reasoning methods of domain-based model consistency. Thus, several domain constraint instances are defined and different models instances’ consistency are reasoned based on formalization of software architecture domain metamodel to illustrate our approach. Finally, our formal definition mechanism of domain constraint is added to our automatic translator for formalizing DSML and its models to automatically reason about domain constraints built based on DSML.

Research on Construction Method of Semantic Dictionary in Architecture

Creating a semantic dictionary is an important means of solving semantic problems in the BIM core technology system, and it is one of the cores of the application of BIM technology in the architectural field. At present, the research on IFD-like libraries in China is still in its infancy. How to construct a semantic dictionary suitable for the needs of the domestic civil engineering field is one of the key issues in domestic BIM technology research. In response to this problem, this paper proposes a method of constructing an IFD Library based on the ontology of the architectural domain. Firstly, it discusses the basic problems of IFD Library-like, then analyzes the root causes of semantic ambiguity in the application of BIM technology and the methods to solve semantic ambiguity, and finally explores and verifies the method of how to construct IFD-like Library based on the ontology of the architectural domain.

Influence of Business Process Maturity Model as a Business Architecture Planning Proposal

This research is a part of previous research that succeeded in producing business model architecture planning, the purpose of this study was to develop previous research using the measurement method of business model maturity as a proposed business model architecture planning concept. By taking the same case study theme as the Tiara Payung Putra (TPP) company. TPP is known as a distributor company in cooperation with Pertamina (Bulk LPG Freight and Filling Station). TPP's main business activity is distributing goods in the form of LPG to 76 bases spread across Balaraja district. The current condition of the business model architecture illustrates the business activities that exist in the TPP. The main problems that occur in TPP are not integrating external systems with internal business activities in the company, and lack of IT resource support. For this reason, the Business Process Maturity Model is needed as a benchmark, which can be proposed as a business architecture planning concept. The business process maturity model process is supported by data validation obtained through respondents, namely business stakeholders in TPP, the process for validating the data by distributing the Assessment questionnaire consisting of 8 Parts the Business Process Assessment model, and 3 Parts for IT Application Readiness Assessment. support of the Enterprise Architecture Planning (EAP) Framework method which focuses on the business model architecture domain. The architecture of the business model illustrates how TPP carries out business activities and functions to achieve its objectives. The results of this study produce the proposed business model architecture planning concept in the form of Business Model Maturity Level Measurement, the IS / IT architecture concept, and the Business Architecture Planning roadmap, which are beneficial for the Tiara Payung Putra (TPP) company for the business model architectural planning

Ontology-Based Semantic Conceptualisation of Historical Built Heritage to Generate Parametric Structured Models from Point Clouds

Nowadays, cultural and historical built heritage can be more effectively preserved, valorised and documented using advanced geospatial technologies. In such a context, there is a major issue concerning the automation of the process and the extraction of useful information from a huge amount of spatial information acquired by means of advanced survey techniques (i.e., highly detailed LiDAR point clouds). In particular, in the case of historical built heritage (HBH) there are very few effective efforts. Therefore, in this paper, the focus is on establishing the connections between semantic and geometrical information in order to generate a parametric, structured model from point clouds using ontology as an effective approach for the formal conceptualisation of application domains. Hence, in this paper, an ontological schema is proposed to structure HBH representations, starting with international standards, vocabularies, and ontologies (CityGML-Geography Markup Language, International Committee for Documentation conceptual reference model (CIDOC-CRM), Industry Foundation Classes (IFC), Getty Art and Architecture Thesaurus (AAT), as well as reasoning about morphology of historical centres by analysis of real case studies) to represent the built and architecture domain. The validation of such schema is carried out by means of its use to guide the segmentation of a LiDAR point cloud from a castle, which is later used to generate parametric geometries to be used in a historical building information model (HBIM).

Optimal Combination of External Wall Insulation Thickness and Surface Solar Reflectivity of Non-Residential Buildings in the Korean Peninsula

To delay fossil energy depletion and implement the Paris Climate Change Accord, the South Korean government is attempting to reduce greenhouse gas emissions with the establishment of the 2030 Roadmap. The insulation performance of external walls is being continuously enhanced in the architectural domain. However, Korea’s policy and construction market focuses only on the heat resistance of buildings’ external walls to enhance the insulation performance, leading to an increased thickness of the insulation materials. In this study, the relationship between the surface reflectivity and insulation thickness of external walls was examined to formulate an effective insulation strategy for buildings in Korea. Office buildings of 12 regions in the Korean Peninsula were considered. The dynamic energy simulation program EnergyPlus was used to perform the heating and cooling load analyses. The present worth method was adopted to perform the economic analysis. The analysis of the cooling and heating loads indicated that a change occurred not only in terms of the latitude but also between the Eastern and Western regions. The energy consumption could be reduced by increasing the reflectivity in the Southern region and lowering the reflectivity in the Northern region, based on the total load. In addition, a higher latitude corresponded to a higher energy saving effect owing to the increased insulation thickness. In the case of Jeju Island and Busan, regions with a relatively large cooling load and small heating load, the total load is little affected by insulation thickness at high reflectivity. If the external skin was considered to have the optimal reflectivity, the regions for optimal insulation thickness could be divided into three categories: north, central and south.

Design and Fabrication of Low Cost 3D Printer

3D printing technology is one type of additive manufacturing processing in which three dimensional solid objects can be created by consecutive layers. It is often referred as rapid prototyping. In this process, 3D models are easily generated on a relatively sized system linked to a device containing object blueprints where this idea of custom production is an exciting one. By using of inkjet printing technology, this innovative approach for making 3D models saves time. To create an overall structure in its own way this technology is often preferred. The major part used to develop a pattern is the cartridge which can be used in most applications such as jewellery design, Architecture domain, Health care, and Engineering. Most required design is created with the help of Computer-Aided Design or 3D Scanner where the cost of a 3D printer is merely high; so a cost-effective low-cost 3D printer with suitable components is fabricated.

Cooked Air

Since 1996, ASHRAE Standard 62.2 has provided guidelines for residential ventilation. As ventilation becomes increasingly scientised, quantifiable, and reliant on hyper-specific equipment, technical literacy on ventilation has narrowed. The relationship between architecture, inhabitants and air management has become increasingly reliant on ventilation standards, in turn increasing reliance on technical specialists, and creating a gap in ventilation knowledge. Through an examination of ASHRAE Standard 62.2, this essay asks why is it that, as ventilation processes become increasingly measurable, there is an equal tendency to reverse awareness in relation to the human sensation, when the standard itself underlines the reality of both phenomenal and intellectual knowledge towards air quality assessment. Furthermore, if architecture’s domain centres on formal, aesthetic, and material logics, is an expanded literacy on air management necessary to address mechanical equipment within an architectural domain?

National Tendency in Church Building in the South of Russia from the Middle of the 19<sup>th</sup> to the Beginning of the 20<sup>th</sup> Centuries

The study is dedicated to the church architecture of South of Russia in the 19th and early 20th centuries. South Russia represents one of the most multi-ethnic and culturally and religiously complex regions of Russia. National character thus occupies a central tendency of its church architecture. Through exploring the evolution of Orthodox church construction in the 19th to early 20th centuries, the study presents evidence of how the national expression in church architecture of South Russia developed. Both preserved and lost churches within the administrative boundaries of the Southern Federal District are considered in the study. The study builds on the theoretical basis of in-depth research on the topic, including in articles and monographs by: Borisova E. A., Kirichenko E. I., Prutsyn O. I., Slavina T. A., Shenkov A. S., Lisovsky V. The study expands existing scholarship through a detailed description of religious objects and focuses on "style" and influences. The investigation of influences on the national tendency of the church architecture of South Russia in the chosen period contributes additional material to the understanding of a difficult period in the history of Russian architecture. The question of national tendencies in architecture has received renewed interest from architects, primarily from those who work in the domain of church architecture. This makes the study’s contribution timely. Research methodology included the analysis of theoretical works and archival material. The study includes historical and contemporary illustrations collected by the author during field trips around the region

πτερόν, πτέρυξ, πτερύγιον. A Cultural-Historical Study of a Classical Greek Architectural Term and Derivatives, and their Post-Classical Meaning

πτeρόν, πτέρυξ and πτeρύγιον all stem from the same root, and their primary meaning is connected to birds: “feather”,“wing”, “shoulder blade”. The history of these words is worthy of note for they came into use in the description of Graeco-Egyptian temple complexes and in the nomenclature of Classical architecture. In order to observe the semantic import of theseand related words and expressions across various cultural contexts (Graeco-Egyptian, Classical and Byzantine) this articlepresents and discusses a range of ancient, late antique and Byzantine literary, erudite, archaeological and iconographic sources.This study aims at giving the reader a glimpse into the Greek lexical domain of architecture, by providing insights into some ofthe general mechanisms of its construction, and specifically to illuminate, by way of a cultural-historical investigation of theseterms, ideas of appearance and significance inherent in the Graeco-Egyptian and Classical and Byzantine worlds. This surveysuggests lexical forms as a key research domain for the understanding of the intellectual, social and cultural life of societies.

Monocular 3D reconstruction of sail flying shape using passive markers

We present a method to recover the 3D flying shape of a sail using passive markers. In the navigation and naval architecture domain, retrieving the sail shape may be of immense value to confirm or contest simulation results, and to aid the design of new optimal sails. Our acquisition setup is very simple and low-cost, as it is only necessary to fix a series of printable markers on the sail and register the flying shape in real sailing conditions from a side vessel with a single camera. We reconstruct the average sail shape during an interval where the sailor maintains the sail as stable as possible. The average is further improved by a Bundle Adjustment algorithm. We tested our method in a real sailing scenario and present promising results. Quantitatively, we show the precision in regards to the reconstructed markers area and the reprojected points. Qualitatively, we present feedback from domain experts who evaluated our results and confirmed the usefulness and quality of the reconstructed shape.

General Issues of Applications Architecture Domain Design

Applications architecture domain as a part of enterprise architecture is the baseline of any organizational activity, which main goal is to provide the executional environment for business processes in order to deliver products or services to satisfy customer needs and generate revenue. Nowadays, software engineering projects always begin with the architecture design phase, despite the waterfall or agile methodology is used by a software development team. Applications architecture design is the most important and, at the same time, the most error-prone stage of the whole software engineering project. It is well-known, that design shortcomings made on the applications design phase may increase drastically to testing and maintenance phases. Further costs to defects fixing may be hundred times higher in the later project stages in compare to the design stage on which applications architecture is defined.

An immersive performative architectural design tool with daylighting simulations: a building information modeling-based approach

PurposeIn performative architectural design, daylighting is a crucial design consideration; however, the evaluation of daylighting in the design process can be challenging. Immersive environments (IEs) can create a dynamic, multi-sensory, first-person view in computer-generated environments, and can improve designers' visual perception and awareness during performative design processes. This research addresses the need for interactive and integrated design tools for IEs toward better-performing architectural solutions in terms of daylighting illumination. In this context, building information modeling and performance simulations are identified as critical technologies to be integrated into performative architectural design.Design/methodology/approachThis research adopts a design science research (DSR) methodology involving an iterative process of development, validation and improvement of a novel and immersive tool, HoloArch, that supports design development during daylighting-informed design processes. HoloArch was implemented in a game engine during a spiral software development process. HoloArch allows users to interact with, visualize, modify and explore architectural models. The evaluation is performed in two workshops and a user study. A hybrid approach that combines qualitative and quantitative data collection was adopted for evaluation. Qualitative data analyses involve interviews, while quantitative data analyses involve both daylighting simulations and questionnaires (e.g. technology acceptance model (TAM), presence and system usability scale (SUS)).FindingsAccording to the questionnaire results, HoloArch had 92/100 for SUS, a mean value of 120.4 for presence questionnaire (PQ) and 9.4/10 for TAM. According to the simulation results, all participants improved the given building's daylighting performance using HoloArch. The interviews also indicated that HoloArch is an effective design tool in terms of augmented perception, continuous design processes, performative daylighting design and model interaction. However, challenges still remain regarding the complete integration of tools and simultaneous simulation visualization. The study concludes that IEs hold promising potentials where performative design actions at conceptual, spatial and architectural domains can take place interactively and simultaneously with immediate feedback.Originality/valueThe research integrates building information modeling (BIM), performative daylighting simulations and IEs in an interactive environment for the identification of potentials and limitations in performative architectural design. Different from existing immersive tools for architecture, HoloArch offers a continuous bidirectional workflow between BIM tools and IEs.

Fully Human Tandem CD22-CD19 CAR-T Cells with Superior Sensitivity to Low Antigen Density Derived by Optimization of Co-Stimulation and CAR Architecture

In the treatment of B cell leukemia, relapse due to antigen to loss or downregulation remains a major challenge. Tumor antigen escape may be mitigated by multi-targeting CAR T cells redirected to CD19 and CD22, and possessing a superior sensitivity to low-density antigens. Using lentiviral transduction of primary T cells, flow cytometry, cell-based assays, and xenograft mouse models, we systematically optimized 22-19 CAR architecture and co-stimulatory domains for best functionality. Fully-human tandem 22-19 CARs with co-stimulatory domains derived from 4-1BB, CD28, ICOS, OX40 or CD27, and hinge and transmembrane domains derived from CD8, CD28, or OX40 were evaluated. The tandem targeting ScFv domain orientation 22-19 was selected based on greater expression and cytotoxicity vs 19-22. All CARs achieved high T cell expression (mean 50-90%), and efficient dose-dependent killing of RajiCD19+CD22+, 293TCD19+, 293TCD22+, but not 293TCD19-CD22- target cells, and elaborated IL-2, IFN-γ, and TNF-a in antigen-dependent manner. CARs' potency in vitro varied by co-stimulatory domain: 4-1BB< OX40, ICOS, CD27<CD28, 4-1BB-CD28. The 22-19 tandem CAR with hinge and transmembrane domains (H/TM) derived from CD8 (CD8/CD8) performed as well as the CAR with H/TM CD28/CD28 configuration, whereas configuration OX40/OX40 was superior to CD8/OX40. In RajiCD19+CD22+ mouse xenografts, the potency of tumor rejection by the 2nd generation tandem 22-19 CARs was also dependent on co-stimulatory domain, ranking 4-1 BB<CD27, ICOS<OX40<CD28. Tandem 3rd generation CAR 22-19, combining CD28 and 4-1BB co-stimulation, achieved the greatest anti-tumor effect. In antigen-heterogeneous Raji xenografts of a mixture of CD19-CD22+, CD19+CD22-, and CD19+CD22+ clones, the 22-19 tandem CARs with CD28, OX40 or ICOS co-stimulation mediated rapid and complete tumor rejection, whereas the conventional single-targeting CAR19 or CAR22 enabled tumor progression due to antigen escape. Low antigen density Raji clones were generated by CRISPR-Cas9-mediated disruption of both CD19 and CD22 expression, followed by lentiviral transduction to express a limited number of antigen molecules on the cell surface. When challenged with Raji CD22 low clone in vitro, 2nd generation tandem CARs with CD28 and ICOS co-stimulation, and the 3rd generation tandem CAR combining CD28 and 4-1BB co-stimulatory domains were more effective than 4-1BB-, CD27-, or OX40-containing tandem CARs. Against RajiCD19 low clone, CARs with CD27 and OX40 domains were more effective than CARs with 4-1BB, and CARs with ICOS or CD28 co-stimulation were the most potent. In summary, the fully-human tandem 22-19 CARs incorporating ICOS and CD28 co-stimulatory domains mitigate tumor antigen escape, exhibit robust anti-tumor function in pre-clinical models, enable superior lysis of CD22low and CD19low tumor clones, and may help improve clinical outcomes. Disclosures Hu: Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. Xiong:Lentigen, a Miltenyi Biotec Company: Current Employment. Wu:Lentigen, a Miltenyi Biotec Company: Current Employment. Zhu:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. Dropulic:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. Schneider:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties.

Enterprise Architecture as Explanatory Information Systems Theory for Understanding Small- and Medium-Sized Enterprise Growth

Understanding and explaining small- and medium-sized enterprise (SME) growth is important for sustainability from multiple perspectives. Research indicates that SMEs comprise more than 80% of most economies, and their cumulative impact on sustainability considerations is far from trivial. In addition, for sustainability concerns to be prioritized, an SME has to be successful over time. In most developing countries, SMEs play a major role in solving socio-economic challenges. SMEs are an active research topic within the information systems (IS) discipline, often within the enterprise architecture (EA) domain. EA fundamentally adopts a systems perspective to describe the essential elements of a socio-technical organization and their relationships to each other and to the environment in order to understand complexity and manage change. However, despite rapid adoption originally, EA research and practice often fails to deliver on expectations. In some circles, EA became synonymous with projects that are over-budget, over-time and costly without the expected return on investment. In this paper, we argue that EA remains indispensable for understanding and explaining enterprises and that we fundamentally need to revisit some of the applications of EA. We, therefore, executed a research study in two parts. In the first part, we applied IS theory perspectives and adopted the taxonomy and structural components of theory to argue that EA, as represented by the Zachman Framework for Enterprise Architecture (ZFEA), could be adopted as an explanatory IS theory. In the second part of the study, we subsequently analysed multiple case studies from this theoretical basis to investigate whether distinguishable focus patterns could be detected during SME growth. The final results provide evidence that EA, represented through an appropriate framework like the ZFEA, could serve as an explanatory theory for SMEs during start-up, growth and transformation. We identified focus patterns and from these results, it should be possible to understand and explain how SMEs grow. Positioning the ZFEA as explanatory IS theory provides insight into the role and purpose of the ZFEA (and by extension EA), and could assist researchers and practitioners with mediating the challenges experienced by SMEs, and, by extension, enhance sustainable development.

Genome-wide identification of toll-like receptors in Pacific white shrimp (Litopenaeus vannamei) and expression analysis in response to Vibrio parahaemolyticus invasion

Genes encoding for Toll-like receptors (TLRs) provide innate immunity to aquatic organisms. The function of TLRs in innate immunity has been characterized in several crustacean species; however, systematic information on TLRs is still scarce in the Pacific white shrimp (Litopenaeus vannamei). Here, we conducted a genome-wide study of TLR genes for the first time in Pacific white shrimps. A total of 11 TLR genes were recognized. Analysis of the architecture domain revealed that most TLR genes possessed three major domains: a Toll/interleukin receptor (TIR) domain, a transmembrane domain (TM), and multiple leucine-rich repeat domains (LRRs). Results revealed that all 11 TLR genes were ubiquitously expressed in all the tested tissues. Furthermore, the expression of 11 TLR genes after Vibrio parahaemolyticus infection was measured in hemocytes, hepatopancreas, and gills. The results showed that most genes were significantly up regulated at different time points, except for TLR-Tollo1 and TLR-Tollo2 in hepatopancreas, and TLR13× isoform, TLR3, TLR4, and PTL-2 in gills. Our study provided the first genome-wide systemic analysis of Pacific white shrimp and suggested that TLR genes play significant roles in the L. vannamei immune response. These findings will offer evidence for the functional study of L. vannamei TLRs and could facilitate the investigation of molecular mechanisms underlying the immune regulation of L. vannamei challenged by V. parahaemolyticus, which will consequently contribute to the sustainability of aquaculture.

In Trail of the Clash of two Civilizations

Nature is full of mysteries which compel one to explore the hidden passages. The passionate urge might take a traveller into the deepest corners of forgotten lands which have truths to be unraveled. Each and every space dynamics has its own temporality and ideological framework which shapes the entire course of ones ideas. The paper will talk about the travelling account of Che Guevara captured in his memoir The Motorcycle Diaries. The book traces the early travels of this Marxist revolutionary. The idea behind is to mark the curvature of topological transformation and its impact on the ideological framework of a person. The paper will explore the interconnections and impact of different spaces encountered during a travel and the nature of discourse which develops during such explorations. Ideas have a disposition to travel with the moving discourse where the architectural domain shapes the outline of the traveller’s thought process. Here Che Guevara’s trip through South America will portray the flow of ideas through different spaces formulating the base for his revolutionary ideas. Through the account of Francisco Pizarro during the conquest of Incan civilization and through the impact of this event on the civilization as a collective whole, the paper will attempt to analyze the ethical curvature of two distinct civilizations, namely the Incan and the Christian Imperial West. The conquest of the South American continent and the consequent clash was cataclysmic, as the socio-economic subversion is still embedded almost non- retrievably deep in terms of its collateral. The paper will include “Heights of Machu Picchu” by Pablo Neruda which again is set during his travelling account to Machu Picchu, which is the marker of a lost civilization where the distorted architecture echoes the richness and the loss at the same time.

The Reuse of Waste Heaps from Extraction Sites: An Architectural Methodology

Nowadays, the rehabilitation of quarries is a widespread practice. It stems from the most significant environmental concern in the management of non-renewable resources. However, reusing quarry waste in the process of regeneration represents the aspect less prevalent. This procedure results from the non-commercialized material, accumulated in huge piles of waste, that constitute invasive elements of the landscape. Because of the intense industrial activity, the wastes further contribute to the degradation of the sites. The result of the waste abandonment could be reversed if this discarded material is considered as a product in the landscape requalification process. Mixing theoretical concepts with practical examples, this article proposes an application methodology to reuse the waste material in the landscape and architectural domains. This new contribution highlights the importance of considering scrap accumulations as an integral part of the architectural project, filling the existing gap in both architectural and theoretical domains. There is not any similar schematization in the literature and the idea of dealing with the mounds of wastes has been only slightly approached until now. The reached outcomes are demonstrative of the possibility of working with the waste heaps in architecture, creating a solid basis for further investigations not documented yet.

Programmable Porous Polymers via Direct Bubble Writing with Surfactant-Free Inks.

Fabrication of macroporous polymers with functionally graded architecture or chemistry bears transformative potential in acoustic damping, energy storage materials, flexible electronics, and filtration but is hardly reachable with current processes. Here, we introduce thiol–ene chemistries in direct bubble writing, a recent technique for additive manufacturing of foams with locally controlled cell size, density, and macroscopic shape. Surfactant-free and solvent-free graded three-dimensional (3D) foams without drying-induced shrinkage were fabricated by direct bubble writing at an unparalleled ink viscosity of 410 cP (40 times higher than previous formulations). Functionalities including shape memory, high glass transition temperatures (>25 °C), and chemical gradients were demonstrated. These results extend direct bubble writing from aqueous inks to nonaqueous formulations at high liquid flow rates (3 mL min−1). Altogether, direct bubble writing with thiol–ene inks promises rapid one-step fabrication of functional materials with locally controlled gradients in the chemical, mechanical, and architectural domains.

Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations.

Long non-coding RNA (lncRNA), which is a kind of noncoding RNA, is generally characterized as being more than 200 nucleotide transcripts in length. LncRNAs exhibit many biological activities, including, but not limited to, cancer development. In this review, a search of the PubMed database was performed to identify relevant studies published in English. The term “lncRNA or long non-coding RNA” was combined with a range of search terms related to the core focus of the review: mechanism, structure, regulation, and cancer. The eligibility of the retrieved studies was mainly based on the abstract. The decision as to whether or not the study was included in this review was made after a careful assessment of its content. The reference lists were also checked to identify any other study that could be relevant to this review. We first summarized the molecular mechanisms of lncRNAs in tumorigenesis, including competing endogenous RNA (ceRNA) mechanisms, epigenetic regulation, decoy and scaffold mechanisms, mRNA and protein stability regulation, transcriptional and translational regulation, miRNA processing regulation, and the architectural role of lncRNAs, which will help a broad audience better understand how lncRNAs work in cancer. Second, we introduced recent studies to elucidate the structure of lncRNAs, as there is a link between lncRNA structure and function and visualizing the architectural domains of lncRNAs is vital to understanding their function. Third, we explored emerging evidence for regulators of lncRNA expression, lncRNA turnover, and lncRNA modifications (including 5-methylcytidine, N6-methyladenosine, and adenosine to inosine editing), highlighting the dynamics of lncRNAs. Finally, we used autophagy in cancer as an example to interpret the diverse mechanisms of lncRNAs and introduced clinical trials of lncRNA-based cancer therapies.

A histone code for inducible transcription in immune responses

Abstract Complex organisms have been subjected to intense selective pressure by host-pathogen coevolution to adapt robust immune responses to pathogen sensing. These responses occur by inducing specific genes within the context of large genomes condensed into chromatin. Despite general description of the chromatin changes that occur across inducible genes, little is known of how specific chromatin features, including histone post-translational modifications (PTM), functionally contribute to transcriptional output of responsive genes. We have described two “signaling-to-chromatin” pathways leading to phosphorylation of histone H3 at residues S28 and S31 that are “read out” by chromatin regulatory factors to augment transcription. H3S28 phosphorylation drives early chromatin activation preceding transcription. This modification delineates expansive chromatin architectural domains containing responsive genes. We are pursuing the hypothesis that H3S28 phosphorylation increases chromatin interaction dynamics within the compartment to favor specific enhancer-promoter interactions and concentrate transcription factors. H3.3S31 is co-transcriptionally phosphorylated along the bodies of induced genes, and coordinately stimulates co-activators and ejects repressors to augment transcription. We hypothesize that these stimulation-dependent histone phosphorylations act synergistically as a dedicated histone code selectively employed at stimulation responsive genes in macrophages and B cells, with potential for involvement in diverse cell types. Our data suggest that co-option of these signaling pathways may contribute to lymphomagenesis, and their disruption could represent novel therapeutic strategies.