Food Lion and the Media’s Liability for Newsgathering Torts: A Symposium Preview

Abans de l'arribada de Pere Alberch a la catedral de Barcelona, el magisteri de l'orgue havia estat en mans de l'organista Joan Ferrer, el qual l'exercí entre 1515 i 1536, essent mestre de cant entre 1513 i 1517. La identitat de l'organista de la catedral de Barcelona correspon a la del compositor «Johannes Ffarer», autor del motet «Domine non secundum» del Cancionero musical de Segovia (CMS). La identificació entre «Johannes Ffarer» i Joan Ferrer, i la presència del seu motet processional «Domine non secundum» juntament amb la de l'himne «Conditor alme siderunt» de Marturià Prats, fan palesa la recepció que la capella flamenca va fer del repertori polifònic d'aquests dos compositors catalans, les obres dels quals es devien incorporar al cançoner durant el prolongat sojorn que la capella de Carles I va fer a Barcelona, en el transcurs de l'any 1519. D'altra banda, i gràcies a la documentació capitular de les seus de Vic, Tortosa i Tarragona, sabem que Marturià Prats, i també Antoni Marlet, romanien vinculats a la capella nobiliària que l'infant Enric, comte d'Empúries, mantenia al seu palau del carrer Ample de Barcelona. En el marc del context urbà, social i musical de la Barcelona de principis del segle xvi no costa gaire d'imaginar com devien sovintejar els contactes, i, amb ells, les avinences i els intercanvis musicals en- tre els músics de la capella flamenca i els de les capelles nobiliàries dels Cardona, l'infant Enric, els Montcada, a banda dels cantors de la catedral i dels de les grans parròquies de la ciutat. Un esdeveniment d'aquestes característiques pot ajudar a explicar el motiu de la presència de les dues obres de Joan Ferrer i Marturià Prats en el CMS, convivint amb la riquesa del seu repertori francoflamenc i castellà.Before Pere Alberch arrived at Barcelona Cathedral, the organ master had been the organist Joan Ferrer in the period between 1515 and 1536, and he had also been the magister cantus between 1513 and 1517. The identity of the organist of Barcelona Cathedral corresponds to that of the composer Johannes Ffarer, who was the author of the motet Domine non secundum of the Cancionero musical de Segovia. The identification between Johannes Ffarer and Joan Ferrer, and the presence of his processional motet Domine non secundum together with that of the hymn Conditor alme siderunt of Marturià Prats, evidence the Flemish chapel's reception of the polyphonic repertoire of these two Catalan composers, whose works must have been added to the cancionero or song-book during the long stay of Charles I's chapel in Barcelona in the course of the year 1519. Moreover, thanks to the chapter documents of the cathedrals of Vic, Tortosa and Tarragona, we know that Marturià Prats as well as Antoni Marlet remained attached to the noble chapel which Prince Henry, Count of Empúries, kept in his palace at Carrer Ample in Barcelona. Within the urban, social and musical context of the Barcelona of the early 16th century, it is easy to imagine how frequent the contacts must have been and consequently the understandings and musical exchanges between the musicians of the Flemish chapel and those of the noble chapels of the Cardonas, Prince Henry, the Montcadas, etc., as well as the singers of the Cathedral and those of the major parish churches of the city. An event of this type could help to explain the reason for the presence of the two works of Joan Ferrer and Marturià Prats in the CMS, together with the rich Franco-Flemish and Castilian repertoire to be found there

Population-average mediation analysis for zero-inflated count outcomes

Mediation analysis is an increasingly popular statistical method for explaining causal pathways to inform intervention. While methods have increased, there is still a dearth of robust mediation methods for count outcomes with excess zeroes. Current mediation methods addressing this issue are computationally intensive, biased, or challenging to interpret. To overcome these limitations, we propose a new mediation methodology for zero-inflated count outcomes using the marginalized zero-inflated Poisson (MZIP) model and the counterfactual approach to mediation. This novel work gives population-average mediation effects whose variance can be estimated rapidly via delta method. This methodology is extended to cases with exposure-mediator interactions. We apply this novel methodology to explore if diabetes diagnosis can explain BMI differences in healthcare utilization and test model performance via simulations comparing the proposed MZIP method to existing zero-inflated and Poisson methods. We find that our proposed method minimizes bias and computation time compared to alternative approaches while allowing for straight-forward interpretations.Comment: 34 pages, 2 figures, 4 tables, 49 pages of Supplemental material, 2 supplemental figure

The embryonic transcription cofactor LBH is a direct target of the Wnt signaling pathway in epithelial development and in aggressive basal subtype breast cancers

Limb-bud and heart (LBH) is a novel key transcriptional regulator of vertebrate development. However, the molecular mechanisms upstream of LBH and its role in adult development are unknown. Here we show that in epithelial development, LBH expression is tightly controlled by Wnt signaling. LBH is transcriptionally induced by the canonical Wnt pathway, as evident by the presence of conserved functional T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) binding sites in the LBH locus and rapid β-catenin-dependent upregulation of endogenous LBH by Wnt3a. In contrast, LBH induction by Wnt/β-catenin signaling is inhibited by Wnt7a, which in limb development signals through a noncanonical pathway involving Lmx1b. Furthermore, we show that LBH is aberrantly overexpressed in mammary tumors of mouse mammary tumor virus (MMTV)-Wnt1-transgenic mice and in aggressive basal subtype human breast cancers that display Wnt/β-catenin hyperactivation. Deregulation of LBH in human basal breast cancer appears to be Wnt/β-catenin dependent, as DKK1 and Wnt7a inhibit LBH expression in breast tumor cells. Overexpression studies indicate that LBH suppresses mammary epithelial cell differentiation, an effect that could contribute to Wnt-induced tumorigenesis. Taken together, our findings link LBH for the first time to the Wnt signaling pathway in both development and cancer and highlight LBH as a potential new marker for therapeutically challenging basal-like breast cancers

Potential biomarkers to predict return to fertility after discontinuation of female contraceptives—looking to the future

Nowadays there are multiple types of contraceptive methods, from reversible to permanent, for those choosing to delay pregnancy. Misconceptions about contraception and infertility are a key factor for discontinuation or the uptake of family planning methods. Regaining fertility (the ability to conceive) after contraceptive discontinuation is therefore pivotal. Technical studies to date have evaluated return to fertility by assessing pregnancy as an outcome, with variable results, or return to ovulation as a surrogate measure by assessing hormone levels (such as progesterone, LH, FSH) with or without transvaginal ultrasound. In general, relying on time to pregnancy as an indicator of return to fertility following contraceptive method discontinuation can be problematic due to variable factors independent of contraceptive effects on fertility, hormone clearance, and fertility recovery. Since the ability to conceive after contraceptive method discontinuation is a critical factor influencing product uptake, it is important to have robust biomarkers that easily and accurately predict the timing of fertility return following contraception and isolate that recovery from extrinsic and circumstantial factors. The main aim of this review is to summarize the current approaches, existing knowledge, and gaps in methods of evaluating return-to-fertility as well as to provide insights into the potential of new biomarkers to more accurately predict fertility restoration after contraceptive discontinuation. Biomarker candidates proposed in this document include those associated with folliculogenesis, cumulus cell expansion, follicular rupture and ovulation, and endometrial transport and receptivity which have been selected and scored on predefined criteria meant to evaluate their probable viability for advancement. The review also describes limitations, regulatory requirements, and a potential path to clinically testing these selected biomarkers. It is important to understand fertility restoration after contraceptive method discontinuation to provide users and health providers with accurate evidence-based information. Predictive biomarkers, if easy and low-cost, have the potential to enable robust evaluation of RTF, and provide potential users the information they desire when selecting a contraceptive method. This could lead to expanded uptake and continuation of modern contraception and inform the development of new contraceptive methods to widen user's family planning choices

PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer

Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers

MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma

Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtypespecific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM

SUMO chain formation is required for response to replication arrest in S. pombe

SUMO is a ubiquitin-like protein that is post-translationally attached to one or more lysine residues on target proteins. Despite having only 18% sequence identity with ubiquitin, SUMO contains the conserved betabetaalphabetabetaalphabeta fold present in ubiquitin. However, SUMO differs from ubiquitin in having an extended N-terminus. In S. pombe the N-terminus of SUMO/Pmt3 is significantly longer than those of SUMO in S. cerevisiae, human and Drosophila. Here we investigate the role of this N-terminal region. We have used two dimensional gel electrophoresis to demonstrate that S. pombe SUMO/Pmt3 is phosphorylated, and that this occurs on serine residues at the extreme N-terminus of the protein. Mutation of these residues (in pmt3-1) results in a dramatic reduction in both the levels of high Mr SUMO-containing species and of total SUMO/Pmt3, indicating that phosphorylation of SUMO/Pmt3 is required for its stability. Despite the significant reduction in high Mr SUMO-containing species, pmt3-1 cells do not display an aberrant cell morphology or sensitivity to genotoxins or stress. Additionally, we demonstrate that two lysine residues in the N-terminus of S. pombe SUMO/Pmt3 (K14 and K30) can act as acceptor sites for SUMO chain formation in vitro. Inability to form SUMO chains results in aberrant cell and nuclear morphologies, including stretched and fragmented chromatin. SUMO chain mutants are sensitive to the DNA synthesis inhibitor, hydroxyurea (HU), but not to other genotoxins, such as UV, MMS or CPT. This implies a role for SUMO chains in the response to replication arrest in S. pomb