Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation

This work was funded by the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk] JQ (BB/K016393/1); AJPB (BB/K017365/1). The work was also supported by the Wellcome Trust [www.wellcome.ac.uk], JQ (086048, 097377); AJPB (097377)); LPE (097377). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities

SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.CA164245 - NCI NIH HHS; R01 CA101992 - NCI NIH HHS; R21 CA129046 - NCI NIH HHS; R21 CA141036 - NCI NIH HHS; P50 GM067041 - NIGMS NIH HHS; UL1RR025771 - NCRR NIH HHS; CA101992 - NCI NIH HHS; UL1 RR025771 - NCRR NIH HHS; GM-073855 - NIGMS NIH HHS; CA129046 - NCI NIH HHS; R21 CA164245 - NCI NIH HHS; GM-067041 - NIGMS NIH HHS; CA141036 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HH

Employer choice and job quality : workplace innovation, work redesign and employee perceptions of job quality in a complex healthcare setting

This article examines employer choice in relation to job quality (JQ). Acknowledging the important role of market, institutional and technological constraints, we highlight the role of employer agency in shaping JQ by reporting on an employer-led service redesign initiative in hospital pharmacy services in Scotland. This redesign initiative aimed at upskilling employees and redirecting their work effort towards high value added, patient-facing work using robotics implementation. The article provides a critical assessment of the success of the initiative in enhancing JQ and explores a range of factors constraining and shaping employers' job quality choices

SYSTEMS AND STRUCTURES OF THE JINAYAT QANUN AND ITS OPPOSING TEXTS

The Jinayat Qanun (JQ) as one of the qanuns issued and enforced by the Governments in the Aceh Province has resulted in opposing views by the stake holders at the provincial and national levels.  The JQ and its opposing texts need studying by which objective descriptions can be obtained for the purpose of developmenal programs at the Aceh Province as a part of the Republic of Indonesia.  This study is based on linguistic theories, which objectively describes the system, structure and linguistic realizations of the JQ and its opposing texts.  This is a qualitatively descriptive study with texts, and descriptions of social contexts of the texts as the data.  The data were obtained by collecting the JQ and its opposing texts and interviews.  The data were then analyzed by using theories of text analysis commonly used in systemic functional linguistic (SFL) theories.  The findings show that each of the two kinds of text has its own different system, stucture and linguistic realizations as each of which is related to different functions and social contexts.  In other words, there have been various understandings of the two texts.  By the various understandings of the two texts, views of the stake holders form proportionally; a condition which is highly needed in Indonesia as a democratic country.  Key Words: qanun jinayat, Aceh, opposing view

Fracture Toughness: Evaluation of Testing Procedure To Simplify JIc Calculations

The purpose of this study is to examine the current fracture toughness test procedure and to determine if there is an easier, less complicated method to get the JIc value from a test record for fracture toughness specimens. The current method for constructing JIc is complicated and involves a detailed computer program or spreadsheet. The objective in this study is to simplify the analysis for the determination of JQ. This study has shown that the load and displacement record for a fracture toughness specimen can be used to directly estimate a JQ value, a provisional value for fracture toughness, JIc. The maximum load point is used along with an adjustment factor for this direct estimation of the JQ value. This JQ value is equivalent to that obtained from the construction procedure, when a unit-sized specimen is tested, that is, a specimen with a width of 50 millimeters (2 inches) and a thickness of 25 millimeters (1 inch). Other sizes require a size adjustment factor, which is simply a function of the specimen width relative to the unit width. The adjustment factor proposed is a square root relationship between the width of the test specimen and a unit width. This shows that the effort required for the proposed new method of constructing JIc is less than that required for the construction method, the new method is simple in concept and requires a minimum number of calculations, and the method appears to produce values of JQ which are comparable to those obtained from the construction procedure and may have less inherent scatter

The Fourth Law of Black Hole Thermodynamics

We show that black holes fulfill the scaling laws arising in critical transitions. In particular, we find that in the transition from negative to positive values the heat capacities $C_{JQ}$, $C_{\Omega Q}$ and $C_{J\Phi}$ give rise to critical exponents satisfying the scaling laws. The three transitions have the same critical exponents as predicted by the universality Hypothesis. We also briefly discuss the implications of this result with regards to the connections among gravitation, quantum mechanics and statistical physics.Comment: 19 pages (two figures), Plain Tex. Preprint KONS-RGKU-93-11. To appear in Nucl. Phys. B (1993

Do holistic human resource management practices make a difference to fly-in fly-out workers’ job quality? An exploratory investigation

In common with ongoing research into human resource management (HRM), there are attributes of jobs that are associated with job quality, which are considered important in attracting and retaining employees. To date, however, analysis has omitted the fly-in fly-out (FIFO) workforce. It is important to consider whether it is possible to develop a strategic HRM approach for FIFO workers where commuting arrangements deviate from the norm. This article fills a gap in the literature by using a four-dimensional job-quality(JQ) framework to analyse factors associated with job quality and HRM. There search was undertaken at two FIFO-dependent workplaces in Western Australia. The findings show that one workplace was using bundles of HR practices that spanned all four JQ dimensions; the other concentrated mainly on two dimensions, a consequence which is the potential to lead to suboptimal outcomes for the organisation and their FIFO employees

Large-N estimates of universal amplitudes of the CP^{N-1} theory and comparison with the JQ model

We present computations of certain finite-size scaling functions and universal amplitude ratios in the large-N limit of the CP^{N-1} field theory. We pay particular attention to the uniform susceptibility, the spin stiffness and the specific heat. Field theoretic arguments have shown that the long-wavelength description of the phase transition between the Neel and valence bond solid states in square lattice S=1/2 anti-ferromagnets is expected to be the non-compact CP^1 field theory. We provide a detailed comparison between our field theoretic calculations and quantum Monte Carlo data close to the Neel -VBS transition on a S=1/2 square-lattice model with competing four-spin interactions (the JQ model).Comment: 15 page

Pharmacological inhibition of bromodomain and extra-terminal proteins induces an NRF-2-mediated antiviral state that is subverted by SARS-CoV-2 infection

Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential prophylactics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-mediated antiviral activity and its susceptibility to viral subversion remain incompletely understood. Pretreatment of cells with iBETs inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. The antiviral activity manifested itself by reduced reporter expression of recombinant viruses, and reduced viral RNA quantities and infectious titers in the culture supernatant. While we confirmed JQ-1-mediated downregulation of expression of angiotensin-converting enzyme 2 (ACE2) and interferon-stimulated genes (ISGs), multi-omics analysis addressing the chromatin accessibility, transcriptome and proteome uncovered induction of an antiviral nuclear factor erythroid 2-related factor 2 (NRF-2)-mediated cytoprotective response as an additional mechanism through which JQ-1 inhibits SARS-CoV-2 replication. Pharmacological inhibition of NRF-2, and knockdown of NRF-2 and its target genes reduced JQ-1-mediated inhibition of SARS-CoV-2 replication. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variant, which exhibited resistance to JQ-1 and increased sensitivity to exogenously administered type I interferon (IFN-I), suggesting a minimised need for SARS-CoV-2 ORF6-mediated repression of IFN signalling in the presence of JQ-1. Importantly, JQ-1 exhibited a transient antiviral activity when administered prophylactically in human airway bronchial epithelial cells (hBAECs), which was gradually subverted by SARS-CoV-2, and no antiviral activity when administered therapeutically following an established infection. We propose that JQ-1 exerts pleiotropic effects that collectively induce an antiviral state in the host, which is ultimately nullified by SARS-CoV-2 infection, raising questions about the clinical suitability of the iBETs in the context of COVID-19