JAK-STAT and AKT pathway-coupled genes in erythroid progenitor cells through ontogeny

Background: It has been reported that the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway regulates erythropoietin (EPO)-induced survival, proliferation, and maturation of early erythroid progenitors. Erythroid cell proliferation and survival have also been related to activation of the JAK-STAT pathway. The goal of this study was to observe the function of EPO activation of JAK-STAT and PI3K/AKT pathways in the development of erythroid progenitors from hematopoietic CD34(+) progenitor cells, as well as to distinguish early EPO target genes in human erythroid progenitors during ontogeny. Methods: Hematopoietic CD34(+) progenitor cells, isolated from fetal and adult hematopoietic tissues, were differentiated into erythroid progenitor cells. We have used microarray analysis to examine JAK-STAT and PI3K/AKT related genes, as well as broad gene expression modulation in these human erythroid progenitor cells. Results: In microarray studies, a total of 1755 genes were expressed in fetal liver, 3844 in cord blood, 1770 in adult bone marrow, and 1325 genes in peripheral blood-derived erythroid progenitor cells. The erythroid progenitor cells shared 1011 common genes. Using the Ingenuity Pathways Analysis software, we evaluated the network pathways of genes linked to hematological system development, cellular growth and proliferation. The KITLG, EPO, GATA1, PIM1 and STAT3 genes represent the major connection points in the hematological system development linked genes. Some JAK-STAT signaling pathway-linked genes were steadily upregulated throughout ontogeny (PIM1, SOCS2, MYC, PTPN11), while others were downregulated (PTPN6, PIAS, SPRED2). In addition, some JAK-STAT pathway related genes are differentially expressed only in some stages of ontogeny (STATs, GRB2, CREBB). Beside the continuously upregulated (AKT1, PPP2CA, CHUK, NFKB1) and downregulated (FOXO1, PDPK1, PIK3CG) genes in the PI3K-AKT signaling pathway, we also observed intermittently regulated gene expression (NFKBIA, YWHAH). Conclusions: This broad overview of gene expression in erythropoiesis revealed transcription factors differentially expressed in some stages of ontogenesis. Finally, our results show that EPO-mediated proliferation and survival of erythroid progenitors occurs mainly through modulation of JAK-STAT pathway associated STATs, GRB2 and PIK3 genes, as well as AKT pathway-coupled NFKBIA and YWHAH genes

Light-based technologies for management of COVID-19 pandemic crisis.

The global dissemination of the novel coronavirus disease (COVID-19) has accelerated the need for the implementation of effective antimicrobial strategies to target the causative agent SARS-CoV-2. Light-based technologies have a demonstrable broad range of activity over standard chemotherapeutic antimicrobials and conventional disinfectants, negligible emergence of resistance, and the capability to modulate the host immune response. This perspective article identifies the benefits, challenges, and pitfalls of repurposing light-based strategies to combat the emergence of COVID-19 pandemic

Environmental interventions to reduce fear of crime: systematic review of effectiveness.

BACKGROUND: Fear of crime is associated with negative health and wellbeing outcomes, and may mediate some impacts of the built environment on public health. A range of environmental interventions have been hypothesized to reduce the fear of crime. METHODS: This review aimed to synthesize the literature on the effectiveness of interventions in the built environment to reduce the fear of crime. Systematic review methodology, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance, was used. Studies of environmental interventions which reported a fear of crime outcome and used any prospective evaluation design (randomized controlled trial (RCT), trial or uncontrolled before-and-after study) were included. Eighteen databases were searched. The Hamilton tool was used to assess quality. A narrative synthesis of findings was undertaken. RESULTS: A total of 47 studies were included, 22 controlled and 25 uncontrolled, with total sample sizes ranging from n = 52 to approximately n = 23,000. Thirty-six studies were conducted in the UK, ten studies in the USA and one study in the Netherlands. The quality of the evidence overall is low. There are some indications that home security improvements and non-crime-related environmental improvements may be effective for some fear of crime outcomes. There is little evidence that the following reduce fear of crime: street lighting improvements, closed-circuit television (CCTV), multi-component environmental crime prevention programs or regeneration programs. CONCLUSIONS: There is some evidence for the effectiveness of specific environmental interventions in reducing some indicators of fear of crime, but more attention to the context and possible confounders is needed in future evaluations of complex social interventions such as these

Rapamycin-inspired macrocycles with new target specificity

Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action, in which they form binary complexes with FK506-binding protein (FKBP) through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mechanistic target of rapamycin (mTOR) and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles (named rapafucins) using optimized FKBP-binding domains. Screening of the rapafucin library in human cells led to the discovery of rapadocin, an inhibitor of nucleoside uptake. Rapadocin is a potent, isoform-specific and FKBP-dependent inhibitor of the equilibrative nucleoside transporter 1 and is efficacious in an animal model of kidney ischaemia reperfusion injury. Together, these results demonstrate that rapafucins are a new class of chemical probes and drug leads that can expand the repertoire of protein targets well beyond mTOR and calcineurin.Peer reviewe