Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner.

Objective:Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) and is characterized by biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. One effect of VHL inactivation is hypoxia inducible factor alpha (HIFα)-independent constitutive activation of nuclear factor kappa B (NF-κB) and c-jun N-terminal kinase (JNK). Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition (EMT). The purpose of this study was to determine the biochemical effects of pomegranate juice extracts (PE) on RCC cell lines. Methods:The pre-clinical effects of PE on NF-κB, JNK, and the EMT phenotype were assayed, including its effect on proliferation, anchorage-independent growth, and invasion of pVHL-deficient RCCs. Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs. The effects of PE are concentration-dependent and affect not only biochemical markers of EMT (i.e., cadherin expression) but also functional manifestations of EMT, such as invasion. These effects are manifested within days of exposure to PE when diluted 2000-fold. Highly dilute concentrations of PE (106 dilution), which do not impact these pathways in the short term, were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure. Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small, localized, incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy

Supporting Fathers in Multi-Ethnic Societies: Insights from British Asian Fathers

AbstractThere is concern that current UK policy and intervention aimed at supporting fathers remains primarily informed by dominant White middle-class values and experiences, and therefore fails to respond adequately to the needs of Britain's diverse fathers. This paper contributes to understanding of ethnic diversity in fathering contexts, practices and experiences, by reporting findings from a qualitative study of British Asian fathers, involving in-depth interviews with fifty-nine fathers and thirty-three mothers from Bangladeshi Muslim, Pakistani Muslim, Gujarati Hindu and Punjabi Sikh background, and over eight additional respondents engaged through Key Informant interviews, ethnographic interviews and group discussions. The paper highlights four areas that require greater recognition by policy-makers and practitioners to appropriately meet the needs of fathers from diverse ethnic and socio-economic backgrounds. These are: recognising that fathers and mothers do not necessarily constitute an autonomous unit; appreciating diversity in fathers’ understandings of desirable child outcomes; addressing additional obstacles to achieving similar outcomes for children; and understanding that the boundaries and content of fathering are not universally recognised. Policies that are less normative and more responsive to diversity are essential to ensure that all fathers can be effectively supported.</jats:p

Stability of local secondary structure determines selectivity of viral RNA chaperones

To maintain genome integrity, segmented double-stranded RNA viruses of the Reoviridae family must accurately select and package a complete set of up to a dozen distinct genomic RNAs. It is thought that the high fidelity segmented genome assembly involves multiple sequence-specific RNA–RNA interactions between single-stranded RNA segment precursors. These are mediated by virus-encoded non-structural proteins with RNA chaperone-like activities, such as rotavirus (RV) NSP2 and avian reovirus σNS. Here, we compared the abilities of NSP2 and σNS to mediate sequence-specific interactions between RV genomic segment precursors. Despite their similar activities, NSP2 successfully promotes inter-segment association, while σNS fails to do so. To understand the mechanisms underlying such selectivity in promoting inter-molecular duplex formation, we compared RNA-binding and helix-unwinding activities of both proteins. We demonstrate that octameric NSP2 binds structured RNAs with high affinity, resulting in efficient intramolecular RNA helix disruption. Hexameric σNS oligomerizes into an octamer that binds two RNAs, yet it exhibits only limited RNA-unwinding activity compared to NSP2. Thus, the formation of intersegment RNA–RNA interactions is governed by both helix-unwinding capacity of the chaperones and stability of RNA structure. We propose that this protein-mediated RNA selection mechanism may underpin the high fidelity assembly of multi-segmented RNA genomes in Reoviridae

Better reporting of interventions : template for intervention description and replication (TIDieR) checklist and guide

Peer reviewedPublisher PD

A survey of the parameter space of the compressible liquid drop model as applied to the neutron star inner crust

We present a systematic survey the range of predictions of the neutron star inner crust composition, crust-core transition densities and pressures, and density range of the nuclear `pasta' phases at the bottom of the crust provided by the compressible liquid drop model in the light of current experimental and theoretical constraints on model parameters. Using a Skyrme-like model for nuclear matter, we construct baseline sequences of crust models by consistently varying the density dependence of the bulk symmetry energy at nuclear saturation density, $L$, under two conditions: (i) that the magnitude of the symmetry energy at saturation density $J$ is held constant, and (ii) $J$ correlates with $L$ under the constraint that the pure neutron matter (PNM) EoS satisfies the results of ab-initio calculations at low densities. Such baseline crust models facilitate consistent exploration of the $L$ dependence of crustal properties. The remaining surface energy and symmetric nuclear matter parameters are systematically varied around the baseline, and different functional forms of the PNM EoS at sub-saturation densities implemented, to estimate theoretical `error bars' for the baseline predictions. Inner crust composition and transition densities are shown to be most sensitive to the surface energy at very low proton fractions and to the behavior of the sub-saturation PNM EoS. Recent calculations of the energies of neutron drops suggest that the low-proton-fraction surface energy might be higher than predicted in Skyrme-like models, which our study suggests may result in a greatly reduced volume of pasta in the crust than conventionally predicted.Comment: 37 Pages, 16 figures, accepted for publication in Astrophysical Journal Supplement Serie

Effects of isospin and momentum dependent interactions on liquid-gas phase transition in hot asymmetric nuclear matter

The liquid-gas phase transition in hot neutron-rich nuclear matter is investigated within a self-consistent thermal model using an isospin and momentum dependent interaction (MDI) constrained by the isospin diffusion data in heavy-ion collisions, a momentum-independent interaction (MID), and an isoscalar momentum-dependent interaction (eMDYI). The boundary of the phase-coexistence region is shown to be sensitive to the density dependence of the nuclear symmetry energy with a softer symmetry energy giving a higher critical pressure and a larger area of phase-coexistence region. Compared with the momentum-independent MID interaction, the isospin and momentum-dependent MDI interaction is found to increase the critical pressure and enlarge the area of phase-coexistence region. For the isoscalar momentum-dependent eMDYI interaction, a limiting pressure above which the liquid-gas phase transition cannot take place has been found and it is shown to be sensitive to the stiffness of the symmetry energy.Comment: 6 pages, 4 figures, revised version, to appear in PL

Does Father Know Best? A Formal Model of the Paternal Influence on Childhood Social Anxiety

We explore paternal social anxiety as a specific risk factor for childhood social anxiety in a rational optimization model. In the course of human evolution, fathers specialized in external protection (e.g., confronting the external world) while mothers specialized in internal protection (e.g., providing comfort and food). Thus, children may instinctively be more influenced by the information signaled by paternal versus maternal behavior with respect to potential external threats. As a result, if fathers exhibit social anxiety, children interpret it as a strong negative signal about the external social world and rationally adjust their beliefs, thus becoming stressed. Under the assumption that paternal signals on social threats are more influential, a rational cognitive inference leads children of socially anxious fathers to develop social anxiety, unlike children of socially anxious mothers. We show in the model that mothers cannot easily compensate for anxious paternal behavior, but choose to increase maternal care to maintain the child’s wellbeing. We discuss research directions to test the proposed model as well as implications for the prevention and treatment of child social anxiety

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations

The impact of point mutations in the human androgen receptor : classification of mutations on the basis of transcriptional activity

Peer reviewedPublisher PD