In Silico Trial Approach For Biomedical Products: A Regulatory Perspective

The modern pharmaceutical industry is creating a transition from traditional methods to advanced technologies like artificial intelligence. In the current scenario, continuous efforts are being made to incorporate computational modelling and simulation in drug discovery, development, design, and optimization. With the advancement in technology and modernization, many pharmaceutical companies are approaching in silico trials to develop safe and efficacious medicinal products. To obtain marketing authorization for a medicinal product from the concerned National regulatory Authority, manufacturers must provide evidence for the safety, efficacy, and quality of medical products in the form of in vitro or in vivo methods. However, more recently this evidence was provided to regulatory agencies in the form of modelling and simulation, i.e., in silico evidence. Such evidence (computational or experimental) will only be accepted by the regulatory authorities if it considered as qualified by them and this will require the assessment of the overall credibility of the method. One must consider the scrutiny provided by the regulatory authority to develop or use the new in silico evidence. The United States Food and Drug Administration and European Medicines Agency are the two regulatory agencies in the world that accept and encourage the use of modelling and simulation within the regulatory process. More efforts must be made by other regulatory agencies worldwide to incorporate such new evidence, i.e., modelling and simulation (in silico) within the regulatory process. This review article focuses on the approaches of in silico trials, its verification, validation, and uncertainty quantification involved in the regulatory evaluation of biomedical products that utilize predictive models.

Searching for the mechanism that mediates mefenoxam-acquired resistance in Phytophthora infestans and how it is regulated

Phytophthora infestans, the causal agent of late blight disease of potatoes, is mainly controlled by the use of fungicides. Isolates that are resistant to commonly used fungicides have been reported. Also, several studies show that originally mefenoxam-sensitive isolates acquire resistance to this fungicide when exposed to sub-lethal concentrations. This phenomenon, termed ‘mefenoxam-acquired resistance’, has been observed in different Phytophthora species and seems to be unique to mefenoxam. In this study, we aimed to elucidate the molecular mechanism mediating this type of resistance as well as a possible regulatory process behind it. A combination of computational analyses and experimental approaches was used to identify differentially expressed genes with a potential association to the phenomenon. These genes were classified into seven functional groups. Most of them seem to be associated with a pleiotropic drug resistance (PDR) phenotype, typically involved in the expulsion of diverse metabolites, drugs, or other substances out of the cell. Despite the importance of RNApolI for the constitutive resistance of P. infestans to mefenoxam, our results indicate no clear interaction between this protein and the acquisition of mefenoxam resistance. Several small non-coding RNAs (ncRNAs) were found to be differentially expressed and specifically related to genes mediating the PDR phenotype, thus suggesting a possible regulatory process. We propose a model of the molecular mechanisms acting within the cell when P. infestans acquires resistance to mefenoxam after exposed to sub-lethal concentrations of the fungicide. This study provides important insights into P. infestans’ cellular and regulatory functionalities.

Projecting Backward and Forward on Processes of Organizational Change and Innovation

This essay discusses how views of organizational change and innovation have traditionally focused on planned episodic change that focuses on rational, strategic, top-down and consensus-directed interventions following teleological or regulatory process models. Future scholarship seems to be focusing more on unplanned continuous organizational changes that emphasize experiential, emergent, bottom-up, pluralistic social movements following dialectical and evolutionary models of change. While planned-episodic and unplanned-continuous change may appear to be opposing views of organizational change, they are entangled in one-another, and provide a rich agenda of future scholarship on processes of organizational change and innovation.

Polydatin Ameliorates Osteoporosis via Suppression of the Mitogen-Activated Protein Kinase Signaling Pathway

Purpose: Polydatin (POL) is a natural active compound found in Polygonum multiflorum with reported anti-oxidant and antiviral effects. With the aging population there has been a stark increase in the prevalence of osteoporosis (OP), rendering it an imposing public health issue. The potential effect of POL as a therapy for OP remains unclear. Therefore, we sought to investigate the therapeutic effect of POL in OP and to elucidate the underlying signaling mechanisms in its regulatory process.Methods: The POL-targeted genes interaction network was constructed using the Search Tool for Interacting Chemicals (STITCH) database, and the shared Kyoto Encyclopedia of Genes and Genomes (KEGG). Pathways involved in OP and POL-targeted genes were identified. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate the osteogenic genes and the phosphorylation level in pre-osteoblastic cells. In addition, ALP and alizarin red staining was used to test the effect of POL on extracellular matrix mineralization.Results: Twenty-seven KEGG pathways shared between POL-related genes and OP were identified. MAPK signaling was identified as a potential key mechanism. In vitro results highlighted a definitive anti-OP effect of POL. The phosphorylation levels of MAPK signaling, including p38α, ERK1/2, and JNK, were significantly decreased in this regulatory process.Conclusion: Our results suggest that POL has a promising therapeutic effect in OP. MAPK signaling may be the underlying mechanism in this effect, providing a novel sight in discovering new drugs for OP.

Severity of self-regulation processes in teachers with different types of professional self-attitude

The article, based on the presented empirical material, reveals the problem of professional self-attitude and its types among teachers with different levels of expression of conscious self-regulation. The study covered 157 teachers of comprehensive schools of the Khanty-Mansiysk Autonomous Okrug – Ugra. The age of the examined is from 31 to 45 years. We used the technique “Attitude to yourself as a professional” and the questionnaire “Style of self-regulation of behavior”. On the basis of the obtained results, it was proved that the processes of conscious self-regulation are interconnected with the magnitude of activity and positivity of professional self-attitude of teachers, as well as that subjects with different levels of self-regulation (high, medium and low) differ in the dominant types of attitudes to themselves as a professional. It has been shown that the more developed regulatory processes are, the more active and positive the professional self-presentation of teachers is – a higher level of claims, combined with a positive representation and acceptance of a professional, expressed by the installation on professional self-development. It was revealed that teachers with a low level of self-regulation are distinguished by a passive-negative attitude towards themselves as a professional, while teachers with a high level are characterized by an active-positive attitude towards themselves, with the dominance of positivity, and teachers with an average level of self-regulation have a pronounced balanced professional self-attitude. It has been established that for the regulatory process of “programming”, the installation on professional self-development is of leading importance, while for the regulatory process, “flexibility” is a significant indicator - the idea of oneself as a professional.

Comparative International Fisheries Management

High-seas fisheries are managed by a set of approximate 20 regional fisheries management organizations (RFMOs) that vary in terms of membership, structure, processes, and health of the stocks they manage. These RFMOs have tackled similar challenges in sometimes different and sometimes convergent ways, learning from each other and occasionally collaborating. This chapter gives an overview of the difficulties of international fisheries management; the primary regulatory approaches (and their evolution) in these organizations, such as voting rules and options to opt out of collective regulations; and the efforts to monitor and enforce rules that have been created. Individually and sometimes collectively RFMOs have worked to decrease the ability of states or vessels to fish outside of the regulatory process, including making it difficult for fish caught outside of RFMO rules to find markets, and they have increased the ability to monitor compliance. While some scholars argue that the regional nature of fisheries management causes problems and that there should be fewer organizations regulating international fisheries, RFMOs have resisted consolidation or management collaboration. Ultimately there is still much to be learned about the sources of effectiveness in management of high-seas fisheries.