Risk measure changes and portfolio optimization theory

Imperial Users onl

Regulation of nuclear actin levels and MRTF/SRF target gene expression during PC6.3 cell differentiation

Actin has important functions in both cytoplasm and nucleus of the cell, with active nuclear transport mechanisms maintaining the cellular actin balance. Nuclear actin levels are subject to regulation during many cellular processes from cell differentiation to cancer. Here we show that nuclear actin levels increase upon dif-ferentiation of PC6.3 cells towards neuron-like cells. Photobleaching experiments demonstrate that this increase is due to decreased nuclear export of actin during cell differentiation. Increased nuclear actin levels lead to decreased nuclear localization of MRTF-A, a well-established transcription cofactor of SRF. In line with MRTF-A localization, transcriptomics analysis reveals that MRTF/SRF target gene expression is first transiently activated, but then substantially downregulated during PC6.3 cell differentiation. This study therefore describes a novel cellular context, where regulation of nuclear actin is utilized to tune MRTF/SRF target gene expression during cell differentiation.Peer reviewe

Lamina-associated polypeptide 2 alpha is required for intranuclear MRTF-A activity

Myocardin-related transcription factor A (MRTF-A), a coactivator of serum response factor (SRF), regulates the expression of many cytoskeletal genes in response to cytoplasmic and nuclear actin dynamics. Here we describe a novel mechanism to regulate MRTF-A activity within the nucleus by showing that lamina-associated polypeptide 2 alpha (Lap2 alpha), the nucleoplasmic isoform of Lap2, is a direct binding partner of MRTF-A, and required for the efficient expression of MRTF-A/SRF target genes. Mechanistically, Lap2 alpha is not required for MRTF-A nuclear localization, unlike most other MRTF-A regulators, but is required for efficient recruitment of MRTF-A to its target genes. This regulatory step takes place prior to MRTF-A chromatin binding, because Lap2 alpha neither interacts with, nor specifically influences active histone marks on MRTF-A/SRF target genes. Phenotypically, Lap2 alpha is required for serum-induced cell migration, and deregulated MRTF-A activity may also contribute to muscle and proliferation phenotypes associated with loss of Lap2 alpha. Our studies therefore add another regulatory layer to the control of MRTF-A-SRF-mediated gene expression, and broaden the role of Lap2 alpha in transcriptional regulation.Peer reviewe

Transcriptional networks controlling the cell cycle.

In this work, we map the transcriptional targets of 107 previously identified Drosophila genes whose loss caused the strongest cell-cycle phenotypes in a genome-wide RNA interference screen and mine the resulting data computationally. Besides confirming existing knowledge, the analysis revealed several regulatory systems, among which were two highly-specific and interconnected feedback circuits, one between the ribosome and the proteasome that controls overall protein homeostasis, and the other between the ribosome and Myc/Max that regulates the protein synthesis capacity of cells. We also identified a set of genes that alter the timing of mitosis without affecting gene expression, indicating that the cyclic transcriptional program that produces the components required for cell division can be partially uncoupled from the cell division process itself. These genes all have a function in a pathway that regulates the phosphorylation state of Cdk1. We provide evidence showing that this pathway is involved in regulation of cell size, indicating that a Cdk1-regulated cell size checkpoint exists in metazoans

beta 2-Integrin Adhesion Regulates Dendritic Cell Epigenetic and Transcriptional Landscapes to Restrict Dendritic Cell Maturation and Tumor Rejection

Dendritic cells (DC), the classic antigen-presenting cells of the immune system, switch from an adhesive, phagocytic phenotype in tissues, to a mature, nonadhesive phenotype that enables migration to lymph nodes to activate T cells and initiate antitumor responses. Monocyte-derived DCs are used in cancer immunotherapy, but their clinical efficacy is limited. Here, we show that cultured bone marrow-derived DCs (BM-DC) expressing dysfunctional beta 2-integrin adhesion receptors displayed enhanced tumor rejection capabilities in B16.OVA and B16-F10 melanoma models. This was associated with an increased CD8(+) T-cell response. BM-DCs expressing dysfunctional beta 2-integrins or manipulated to disrupt integrin adhesion or integrin/actin/nuclear linkages displayed spontaneous maturation in ex vivo cultures (increased costimulatory marker expression, IL12 production, and 3D migration capabilities). This spontaneous maturation was associated with an altered DC epigenetic/transcriptional profile, including a global increase in chromatin accessibility and H3K4me3/H3K27me3 histone methylation. Genome-wide analyses showed that H3K4me3 methylation was increased on DC maturation genes, such as CD86, Il12, Ccr7, and Fscn1, and revealed a role for a transcription factor network involving Ikaros and RelA in the integrin-regulated phenotype of DCs. Manipulation of the integrin-regulated epigenetic landscape in wild-type ex vivo-cultured BM-DCs enhanced their functionality in tumor rejection in vivo. Thus, beta 2-integrin-mediated adhesion to the extracellular environment plays an important role in restricting DC maturation and antitumor responses through regulation of the cellular epigenetic and transcriptional landscape. Targeting beta 2-integrins could therefore be a new strategy to improve the performance of current DC-based cancer immunotherapies.Peer reviewe

INTERROGATIVE SENTENCES IN DOCTOR – PATIENT COMMUNICATION IN ENGLISH: SELECTION CRITERIA

Background. Communication between doctor and patient is an important component of the treatment process. The main task of the doctor is to collect all the necessary information about the patient’s problem and the history of its occurrence, to clarify all the circumstances of the situation and to offer options for action. In order to solve this problem, it is necessary to use certain speech means that should help the doctor get all the information and get what they want from the patient. Questions are one of the means that determine the effectiveness of interaction. Purpose. The purpose of the study of this article is to analyze the interrogative sentences used in the doctor – patient dialogues in English, to determine their communicative load, to identify the most frequent constructions and to describe the criteria for choosing the types of interrogative sentences. Materials and methods. The material of the study was the scripts of conversations between doctors and patients in English, presented in open sources. In the course of the study, a continuous sample of interrogative sentences used by the doctor was carried out. The questions were divided into types according to their grammatical structure, the communicative load of each type was determined. The most and least frequent types of questions are singled out, possible grounds for such a pattern are identified. Results. The article describes the main types of questions in English in terms of their grammatical structure: general, special, alternative and disjunctive. The results of own research based on the material of audio recordings and their scripts of conversations between doctors of various specialties and their patients at various stages of the treatment process are presented. In the process of research, each type of questions was analyzed in the context of their use in order to describe their communicative load. This approach made it possible to identify criteria for selecting certain types of questions, which are determined by the target settings of the communicative “doctor-patient” situation. Practical implications. The results of the study can be applied in the practice of teaching Medical English, in the professional activities of healthcare professionals when communicating with patients, in theoretical courses on English grammar