A Methodology for Deriving System Requirements Using Agent Based System Modeling

In this paper, we duscuss a method to derive the requirements for developing an Industrial Automation and Constrol System (IACS). An IACS has software components and associated hardware, which together implement the required monitoring, supervision and control of operations an a production plant. The requirements of such a system are multi-dimensional and may require multiple layers of abstraction. For this domain, we propose an agent-based modeling adopting an agent-based modeling approach is the implicit flexibility afforded by agents and the negotiation techniques that can be implemented to streamline the change management process associated with requirements modeling and analysis. This paper utilizes modeling constructs from UML/SysML to model and visualize the interactions among the agents. The types of agents and their roles are discussed in detail

Kaposi’s Sarcoma Associated Herpesvirus Encoded Viral FLICE Inhibitory Protein K13 Activates NF-κB Pathway Independent of TRAF6, TAK1 and LUBAC

BACKGROUND: Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies

Mutant p53 protects ETS2 from non-canonical COP1/DET1 dependent degradation

Mutations in the tumor suppressor gene TP53 contribute to the development of approximately half of all human cancers. One mechanism by which mutant p53 (mtp53) acts is through interaction with other transcription factors, which can either enhance or repress the transcription of their target genes. Mtp53 preferentially interacts with the erythroblastosis virus E26 oncogene homologue 2 (ETS2), an ETS transcription factor, and increases its protein stability. To study the mechanism underlying ETS2 degradation, we knocked down ubiquitin ligases known to interact with ETS2. We observed that knockdown of the constitutive photomorphogenesis protein 1 (COP1) and its binding partner De-etiolated 1 (DET1) significantly increased ETS2 stability, and conversely, their ectopic expression led to increased ETS2 ubiquitination and degradation. Surprisingly, we observed that DET1 binds to ETS2 independently of COP1, and we demonstrated that mutation of multiple sites required for ETS2 degradation abrogated the interaction between DET1 and ETS2. Furthermore, we demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Mechanistically, we show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. Our study reveals a hitherto unknown function in which DET1 mediates the interaction with the substrates of its cognate ubiquitin ligase complex and provides an explanation for the ability of mtp53 to protect ETS2. </p

Impact on health and provision of healthcare services during the COVID-19 lockdown in India: A multicentre cross-sectional study

Introduction The COVID-19 pandemic resulted in a national lockdown in India from midnight on 25 March 2020, with conditional relaxation by phases and zones from 20 April. We evaluated the impact of the lockdown in terms of healthcare provisions, physical health, mental health and social well-being within a multicentre cross-sectional study in India.Methods The SMART India study is an ongoing house-to-house survey conducted across 20 regions including 11 states and 1 union territory in India to study diabetes and its complications in the community. During the lockdown, we developed an online questionnaire and delivered it in English and seven popular Indian languages (Hindi, Tamil, Marathi, Telegu, Kannada, Bengali, Malayalam) to random samples of SMART-India participants in two rounds from 5 May 2020 to 24 May 2020. We used multivariable logistic regression to evaluate the overall impact on health and healthcare provision in phases 3 and 4 of lockdown in red and non-red zones and their interactions.Results A total of 2003 participants completed this multicentre survey. The bivariate relationships between the outcomes and lockdown showed significant negative associations. In the multivariable analyses, the interactions between the red zones and lockdown showed that all five dimensions of healthcare provision were negatively affected (non-affordability: OR 1.917 (95% CI 1.126 to 3.264), non-accessibility: OR 2.458 (95% CI 1.549 to 3.902), inadequacy: OR 3.015 (95% CI 1.616 to 5.625), inappropriateness: OR 2.225 (95% CI 1.200 to 4.126) and discontinuity of care: OR 6.756 (95% CI 3.79 to 12.042)) and associated depression and social loneliness.Conclusion The impact of COVID-19 pandemic and lockdown on health and healthcare was negative. The exaggeration of income inequality during lockdown can be expected to extend the negative impacts beyond the lockdown

AKT and 14-3-3 regulate Notch4 nuclear localization

Members of the Notch family of transmembrane receptors, Notch1-4 in mammals, are involved in the regulation of cell fate decisions and cell proliferation in various organisms. The Notch4 isoform, which is specific to mammals, was originally identified as a viral oncogene in mice, Int3, able to initiate mammary tumors. In humans, Notch4 expression appears to be associated with breast cancer stem cells and endocrine resistance. Following ligand binding, the Notch4 receptor undergoes cleavage at the membrane and the Notch4-intracellular domain (ICD), translocates to the nucleus and regulates gene transcription. Little is known on the mechanisms regulating Notch4-ICD and its nuclear localization. Here, we describe the identification of four distinct AKT phosphorylation sites in human Notch4-ICD and demonstrate that AKT binds Notch4-ICD and phosphorylates all four sites in vitro and in vivo. The phosphorylation in cells is regulated by growth factors and is sensitive to phosphatidyl inositol-3 kinase (PI3K) inhibitors. This phosphorylation generates binding sites to the 14-3-3 regulatory proteins, which are involved in the regulation of nucleocytoplasmic shuttling of target proteins, restricting phosphorylated Notch4-ICD to the cytoplasm. Our findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling

The ORNATE India project: Building research capacity and capability to tackle the burden of diabetic retinopathy-related blindness in India

The ORNATE India project is an interdisciplinary, multifaceted United Kingdom (UK)–India collaborative study aimed to build research capacity and capability in India and the UK to tackle the burden of diabetes-related visual impairment. For 51 months (October 2017–December 2021), this project built collaboration between six institutions in the UK and seven in India, including the Government of Kerala. Diabetic retinopathy (DR) screening models were evaluated in the public system in Kerala. An epidemiological study of diabetes and its complications was conducted through 20 centers across India covering 10 states and one union territory. The statistical analysis is not yet complete. In the UK, risk models for diabetes and its complications and artificial intelligence-aided tools are being developed. These were complemented by joint studies on various aspects of diabetes between collaborators in the UK and India. This interdisciplinary team enabled increased capability in several workstreams, resulting in an increased number of publications, development of cost-effective risk models, algorithms for risk-based screening, and policy for state-wide implementation of sustainable DR screening and treatment programs in primary care in Kerala. The increase in research capacity included multiple disciplines from field workers, administrators, project managers, project leads, screeners, graders, optometrists, nurses, general practitioners, and research associates in various disciplines. Cross-fertilization of these disciplines enabled the development of several collaborations external to this project. This collaborative project has made a significant impact on research capacity development in both India and the UK

Complex interventions to implement a diabetic retinopathy care pathway in the public health system in Kerala: the Nayanamritham study protocol

Introduction: Using a type 2 hybrid effectiveness-implementation design, we aim to pilot a diabetic retinopathy (DR) care pathway in the public health system in Kerala to understand how it can be scaled up to and sustained in the whole state.Methods and analysis: Currently, there is no systematic DR screening programme in Kerala. Our intervention is a teleophthalmology pathway for people with diabetes in the non-communicable disease registers in 16 family health centres. The planned implementation strategy of the pathway will be developed based on the discrete Expert Recommendations for Implementing Change taxonomy. We will use both quantitative data from a cross-sectional study and qualitative data obtained from structured interviews, surveys and group discussions with stakeholders to report the effectiveness of the DR care pathway and evaluation of the implementation strategy.We will use logistic regression models to assess crude associations DR and sight-threatening diabetic retinopathy and fractional polynomials to account for the form of continuous covariates to predict uptake of DR screening. The primary effectiveness outcome is the proportion of patients in the non-communicable disease register with diabetes screened for DR over 12 months. Other outcomes include cost-effectiveness, safety, efficiency, patient satisfaction, timeliness and equity. The outcomes of evaluation of the implementation strategies include acceptability, feasibility, adoption, appropriateness, fidelity, penetration, costs and sustainability. Addition of more family health centres during the staggered initial phase of the programme will be considered as a sign of acceptability and feasibility. In the long term, the state-wide adoption of the DR care pathway will be considered as a successful outcome of the Nayanamritham study.Ethics and dissemination: The study was approved by Indian Medical Research Council (2018-0551) dated 13 March 2019. Study findings will be disseminated through scientific publications and the report will inform adoption of the DR care pathway by Kerala state in future