Coinage Metal Bis(amidinate) Complexes as Building Blocks for Self‐Assembled One‐Dimensional Coordination Polymers

The pyridyl functionalized amidinate [{PyC≡CC(NDipp)$_{2}$}Li(thf)$_{2}$]n was used to synthesize a series of bis-amidinate complexes [{PyC≡CC(NDipp)$_{2}$}$_{2}$M$_{2}$] (M=Cu, Ag, Au) with fully supported metallophilic interactions. These metalloligands were then used as building blocks for the synthesis of one-dimensional heterobimetallic coordination polymers using Zn(hfac)$_{2}$ (hfac=hexaflouroacetylacetonate) for self-assembly. Interestingly, the three coordination polymers [{PyC≡CC(NDipp)$_{2}$}$_{2}$M$_{2}$][Zn(hfac)$_{2}$] (M=Cu, Ag, Au), exhibit a zig zag shape in the solid state. To achieve linear coordination geometry other connectors such as M’(acac) (M’=Ni, Co) (acac=acetylacetonate) were investigated. The thus obtained compounds [{PyC≡CC(NDipp)$_{2}$}$_{2}$Cu$_{2}$][M’(acac)$_{2}$] (M’=Ni, Co) are indeed linear heterobimetallic coordination polymers featuring a metalloligand backbone with fully supported metallophilic interactions

Stable salts of the hexacarbonyl chromium(I) cation and its pentacarbonyl-nitrosyl chromium(I) analogue

Homoleptic carbonyl radical cations are a textbook family of complexes hitherto unknown in the condensed phase, leaving their properties and applications fundamentally unexplored. Here we report on two stable 17-electron [Cr(CO)6]•+ salts that were synthesized by oxidation of Cr(CO)6 with [NO]+[Al(ORF)4]− (RF = C(CF3)3)) in CH2Cl2 and with removal of NO gas. Longer reaction times led to NO/CO ligand exchange and formation of the thermodynamically more stable 18-electron species [Cr(CO)5(NO)]+, which belongs to the family of heteroleptic chromium carbonyl/nitrosyl cations. All salts were fully characterized (IR, Raman, EPR, NMR, scXRD, pXRD, magnetics) and are stable at room temperature under inert conditions over months. The facile synthesis of these species enables the thorough investigation of their properties and applications to a broad scientific community

TEDI: the TripleSpec Exoplanet Discovery Instrument

The TEDI (TripleSpec - Exoplanet Discovery Instrument) will be the first instrument fielded specifically for finding low-mass stellar companions. The instrument is a near infra-red interferometric spectrometer used as a radial velocimeter. TEDI joins Externally Dispersed Interferometery (EDI) with an efficient, medium-resolution, near IR (0.9 - 2.4 micron) echelle spectrometer, TripleSpec, at the Palomar 200" telescope. We describe the instrument and its radial velocimetry demonstration program to observe cool stars.Comment: 6 Pages, To Appear in SPIE Volume 6693, Techniques and Instrumentation for Detection of Exoplanets II

Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells.</p> <p>Results</p> <p>Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates.</p> <p>Conclusions</p> <p>Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.</p

Robotic Assisted Laparoscopic Prostatectomy Performed after Previous Suprapubic Prostatectomy

Operative management of prostate cancer in a patient who has undergone previous open suprapubic simple prostatectomy poses a unique surgical challenge. Herein, we describe a case of intermediate risk prostate cancer in a man who had undergone simple prostatectomy ten years prior to presentation. The patient was found to have Gleason 7 prostate cancer on MRI fusion biopsy of the prostate for elevated PSA and underwent an uncomplicated robot assisted laparoscopic radical prostatectomy

Sustaining work participation across the life course

Introduction Many disability prevention strategies are focused on acute injuries and brief illness episodes, but there will be growing challenges for employers to manage circumstances of recurrent, chronic, or fluctuating symptoms in an aging workforce. The goal of this article is to summarize existing peer-review research in this area, compare this with employer discourse in the grey literature, and recommend future research priorities. Methods The authors participated in a year-long sponsored collaboration that ultimately led to an invited 3-day conference, “Improving Research of Employer Practices to Prevent Disability”, held October 14–16, 2015, in Hopkinton, Massachusetts, USA. The collaboration included a topical review of the scientific and industry literature, group discussion to identify key areas and challenges, drafting of initial documents, and feedback from peer researchers and a special panel of experts with employer experience. Results Cancer and mental illness were chosen as examples of chronic or recurring conditions that might challenge conventional workplace return-to-work practices. Workplace problems identified in the literature included fatigue, emotional exhaustion, poor supervisor and co-worker support, stigma, discrimination, and difficulties finding appropriate accommodations. Workplace intervention research is generally lacking, but there is preliminary support for improving workplace self-management strategies, collaborative problem-solving, and providing checklists and other tools for job accommodation, ideas echoed in the literature directed toward employers. Research might be improved by following workers from an earlier stage of developing workplace concerns. Conclusions Future research of work disability should focus on earlier identification of at-risk workers with chronic conditions, the use of more innovative and flexible accommodation strategies matched to specific functional losses, stronger integration of the workplace into on-going rehabilitation efforts, and a better understanding of stigma and other social factors at work

DNA copy number alterations in central primitive neuroectodermal tumors and tumors of the pineal region: an international individual patient data meta-analysis

Little is known about frequency, association with clinical characteristics, and prognostic impact of DNA copy number alterations (CNA) on survival in central primitive neuroectodermal tumors (CNS-PNET) and tumors of the pineal region. Searches of MEDLINE, Pubmed, and EMBASE—after the original description of comparative genomic hybridization in 1992 and July 2010—identified 15 case series of patients with CNS-PNET and tumors of the pineal region whose tumors were investigated for genome-wide CNA. One additional case study was identified from contact with experts. Individual patient data were extracted from publications or obtained from investigators, and CNAs were converted to a digitized format suitable for data mining and subgroup identification. Summary profiles for genomic imbalances were generated from case-specific data. Overall survival (OS) was estimated using the Kaplan-Meier method, and by univariable and multivariable Cox regression models. In their overall CNA profiles, low grade tumors of the pineal region clearly diverged from CNS-PNET and pineoblastoma. At a median follow-up of 89months, 7-year OS rates of CNS-PNET, pineoblastoma, and low grade tumors of the pineal region were 22.9±6, 0±0, and 87.5±12%, respectively. Multivariable analysis revealed that histology (CNS-PNET), age (≤2.5years), and possibly recurrent CNAs were associated with unfavorable OS. DNA copy number profiling suggests a close relationship between CNS-PNET and pineoblastoma. Low grade tumors of the pineal region differed from CNS-PNET and pineoblastoma. Due to their high biological and clinical variability, a coordinated prospective validation in future studies is necessary to establish robust risk factor

Phosphorylation of serine 225 in hepatitis C virus NS5A regulates protein-protein interactions.

Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is a phosphoprotein that plays key, yet poorly defined, roles in both virus genome replication and virion assembly/release. It has been proposed that differential phosphorylation could act as a switch to regulate the various functions of NS5A, however the mechanistic details of the role of this post-translational modification in the virus life cycle remains obscure. We previously reported (Ross-Thriepland et al, 2015) a role for phosphorylation at serine 225 (S225) of NS5A in the regulation of JFH-1 (genotype 2a) genome replication. A phosphoablatant (S225A) mutation resulted in a 10-fold reduction in replication and a perinuclear restricted distribution of NS5A, whereas the corresponding phosphomimetic mutation (S225D) had no phenotype. To determine the molecular mechanisms underpinning this phenotype we conducted a label-free proteomics approach to identify cellular NS5A interaction partners. This analysis 30 revealed that the S225A mutation disrupted the interactions of NS5A with a number of cellular proteins, in particular the nucleosome assembly protein 1-like protein 1 (NAP1L1), bridging integrator 1 (Bin1, also known as Amphiphysin II) and vesicle associated membrane protein-associated protein A (VAP-A). These interactions were validated by immunoprecipitation/western blotting, immunofluorescence and proximity ligation assay. Importantly, siRNA-mediated knockdown of NAP1L1, Bin1 or VAP-A impaired viral genome replication and recapitulated the perinuclear redistribution of NS5A seen in the S225A mutant. These results demonstrate that S225 phosphorylation regulates the interactions of NS5A with a defined subset of cellular proteins. Furthermore, these interactions regulate both HCV genome replication and the subcellular localisation of replication complexes. IMPORTANCE Hepatitis C virus is an important human pathogen. The viral nonstructural 5A protein (NS5A) is the target for new antiviral drugs. NS5A has multiple functions during the virus life cycle, but the biochemical details of these roles remain obscure. NS5A is known to be phosphorylated by cellular protein kinases, and in this study, we set out to determine whether this modification is required for the binding of NS5A to other cellular proteins. We identified 3 such proteins and show that they interacted only with NS5A that was phosphorylated on a specific residue. Furthermore, these proteins were required for efficient virus replication and the ability of NS5A to spread throughout the cytoplasm of the cell. Our results help to define the function of NS5A and may contribute to an understanding of the mode of action of the highly potent antiviral drugs that are targeted to NS5A