From the bargaining table to the ballot box: political effects of right to work laws

Labor unions play a central role in the Democratic party coalition, providing candidates with voters, volunteers, and contributions, as well as lobbying policymakers. Has the sustained decline of organized labor hurt Democrats in elections and shifted public policy? We use the enactment of right-to-work laws—which weaken unions by removing agency shop protections—to estimate the effect of unions on politics from 1980 to 2016. Comparing counties on either side of a state and right-to-work border to causally identify the effects of the state laws, we find that right-towork laws reduce Democratic Presidential vote shares by 3.5 percentage points. We find similar effects in US Senate, US House, and Gubernatorial races, as well as on state legislative control. Turnout is also 2 to 3 percentage points lower in right-to-work counties after those laws pass. We next explore the mechanisms behind these effects, finding that right-to-work laws dampen organized labor campaign contributions to Democrats and that potential Democratic voters are less likely to be contacted to vote in right-to-work states. The weakening of unions also has large downstream effects both on who runs for office and on state legislative policy. Fewer working class candidates serve in state legislatures and Congress, and state policy moves in a more conservative direction following the passage of right-to-work laws

Development of an in vitro assay for high-throughput screening investigating the role of mesenchymal stem cells on castration resistant prostate cancer cell growth

Androgen deprivation therapy (ADT) can increase survival from prostate cancer by up to 2-3 years, but tumours invariably relapse into an ADT-unresponsive, incurable form, known as castrate resistant prostate cancer (CRPC). CRPC is more aggressive and more likely to metastasise to bone, worsening morbidity and mortality. Mesenchymal stem cells have been implicated in alteration of androgen signalling within prostate cancer cells and stimulation of metastasis and resistance to anti-tumour therapy, and thus may play an important role in the development of castration resistance. A high throughput screen to identify compounds that inhibit the effect of MSCs on castration resistance would thus be valuable in development of novel chemotherapeutics against CRPC. Clones of the human CWR22PC and murine Myc-CaP Bo prostate cancer cell lines were characterised by their reduced growth in response to androgen deprivation, modelled using charcoal stripped serum and the antiandrogen enzalutamide. Investigations were performed to optimise the miniaturisation of this assay. The effect of conditioned media from human or murine mesenchymal stem cells on this cell growth was then examined in the presence of androgen and androgen deprivation, in a high-throughput format. It was found that MSC-conditioned media had only a small positive effect stimulating growth in CWR22PC cells, greatest in the enzalutamide-treated condition. In the murine Myc-CaP Bo cell line clone 5GSH-6943#5, MSC-conditioned media significantly stimulated castration-resistant growth in the androgen deprivation condition but not in the presence of androgen. However, assay validation indicated that the assay developed for either cell line was not suitable for high-throughput drug screening in its current form. Further optimisation is thus required for use of the assays developed as a platform for high-throughput screening to investigate the effects of various therapeutic compounds on MSC stimulation of castration-resistant prostate cancer cell growth

Cosmic Ray Detection at the Murchison Radio-astronomy Observatory – a pathfinder for SKA-Low

We present the status of cosmic-ray detection activities at the Murchison Radio-astronomy Observatory. Using 128 antennas of the Murchison Widefield Array radio telescope in its extended configuration, we detect the radio emission from extensive air showers in the 122--154 MHz range at a rate of slightly less than once per hour, each with an approximate energy of 10$^{17}$ eV. We have developed a bespoke filter inversion to obtain high-time-resolution data from this general-purpose astronomy instrument, and directly capture the radio signal. Our future plans include the implementation of a particle-triggered mode, and expanded operations with the low-frequency component of the Square Kilometre Array, which will have ~100,000 antennas deployed on the same site

Increased risk of A(H1N1)pdm09 influenza infection in UK pig industry workers compared to a general population cohort

Background: Pigs are mixing vessels for influenza viral reassortment but the extent of influenza transmission between swine and humans is not well understood. Objectives: To assess whether occupational exposure to pigs is a risk factor for human infection with human and swine-adapted influenza viruses. Methods: UK pig industry workers were frequency-matched on age, region, sampling month, and gender with a community-based comparison group from the Flu Watch study. HI assays quantified antibodies for swine and human A(H1) and A(H3) influenza viruses (titres≥40 considered seropositive and indicative of infection). Virus-specific associations between seropositivity and occupational pig exposure were examined using multivariable regression models adjusted for vaccination. Pigs on the same farms were also tested for seropositivity. Results: 42% of pigs were seropositive to A(H1N1)pdm09. Pig industry workers showed evidence of increased odds of A(H1N1)pdm09 seropositivity compared to the comparison group, albeit with wide confidence intervals (CI), Adjusted Odds Ratio after accounting for possible cross reactivity with other swine A(H1) viruses (aOR) 25.30, 95% CI [1.44-536.34], p=0.028. Conclusion: The results indicate that A(H1N1)pdm09 virus was common in UK pigs during the pandemic and subsequent period of human A(H1N1)pdm09 circulation, and occupational exposure to pigs was a risk factor for human infection. Influenza immunization of pig industry workers may reduce transmission and the potential for virus reassortment

A core outcome set for localised prostate cancer effectiveness trials

Objective: To develop a core outcome set (COS) applicable for effectiveness trials of all interventions for localised prostate cancer. Background: Many treatments exist for localised prostate cancer, although it is unclear which offers the optimal therapeutic ratio. This is confounded by inconsistencies in the selection, definition, measurement and reporting of outcomes in clinical trials. Subjects and methods: A list of 79 outcomes was derived from a systematic review of published localised prostate cancer effectiveness studies and semi-structured interviews with 15 prostate cancer patients. A two-stage consensus process involving 118 patients and 56 international healthcare professionals (HCPs) (cancer specialist nurses, urological surgeons and oncologists) was undertaken, consisting of a three-round Delphi survey followed by a face-to-face consensus panel meeting of 13 HCPs and 8 patients. Results: The final COS included 19 outcomes. Twelve apply to all interventions: death from prostate cancer, death from any cause, local disease recurrence, distant disease recurrence/metastases, disease progression, need for salvage therapy, overall quality of life, stress urinary incontinence, urinary function, bowel function, faecal incontinence, sexual function. Seven were intervention-specific: perioperative deaths (surgery), positive surgical margin (surgery), thromboembolic disease (surgery), bothersome or symptomatic urethral or anastomotic stricture (surgery), need for curative treatment (active surveillance), treatment failure (ablative therapy), and side effects of hormonal therapy (hormone therapy). The UK-centric participants may limit the generalisability to other countries, but trialists should reason why the COS would not be applicable. The default position should not be that a COS developed in one country will automatically not be applicable elsewhere. Conclusion: We have established a COS for trials of effectiveness in localised prostate cancer, applicable across all interventions which should be measured in all localised prostate cancer effectiveness trials

Increased risk of A(H1N1)pdm09 influenza infection in UK pig industry workers compared to a general population cohort.

BACKGROUND: Pigs are mixing vessels for influenza viral reassortment, but the extent of influenza transmission between swine and humans is not well understood. OBJECTIVES: To assess whether occupational exposure to pigs is a risk factor for human infection with human and swine-adapted influenza viruses. METHODS: UK pig industry workers were frequency-matched on age, region, sampling month, and gender with a community-based comparison group from the Flu Watch study. HI assays quantified antibodies for swine and human A(H1) and A(H3) influenza viruses (titres ≥ 40 considered seropositive and indicative of infection). Virus-specific associations between seropositivity and occupational pig exposure were examined using multivariable regression models adjusted for vaccination. Pigs on the same farms were also tested for seropositivity. RESULTS: Forty-two percent of pigs were seropositive to A(H1N1)pdm09. Pig industry workers showed evidence of increased odds of A(H1N1)pdm09 seropositivity compared to the comparison group, albeit with wide confidence intervals (CIs), adjusted odds ratio after accounting for possible cross-reactivity with other swine A(H1) viruses (aOR) 25·3, 95% CI (1·4-536·3), P = 0·028. CONCLUSION: The results indicate that A(H1N1)pdm09 virus was common in UK pigs during the pandemic and subsequent period of human A(H1N1)pdm09 circulation, and occupational exposure to pigs was a risk factor for human infection. Influenza immunisation of pig industry workers may reduce transmission and the potential for virus reassortment.This work was supported by joint funding from the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), and the Wellcome Trust (WT) [(BBSRC/MRC/WT) BB/H014306/1; (MRC/WT) MC_U122785833; (MRC) G0800767 and G0600511]; Alborada Trust (to J.L.N.W.); the RAPIDD programme of the Science & Technology Directorate (to J.L.N.W.); US Department of Homeland Security (to J.L.N.W.); and the Fogarty International Center at the National Institutes of Health (to J.L.N.W.). DAI is supported by a fellowship from the National Institute for Health Research (NIHR) (PDF-2012-05-305) (this research is independent and the views expressed in this publication are those of the authors and not necessarily those of the Department of Health or NIHR).This is the final version of the article. It first appeared from Wiley via https://doi.org//10.1111/irv.12364/abstract

Thin, fine and with sensitivity: a metamethodology of intuitions

Do philosophers use intuitions? Should philosophers use intuitions? Can philosophical methods (where intuitions are concerned) be improved upon? In order to answer these questions we need to have some idea of how we should go about answering them. I defend a way of going about methodology of intuitions: a metamethodology. I claim the following: (i) we should approach methodological questions about intuitions with a thin conception of intuitions in mind; (ii) we should carve intuitions finely; and, (iii) we should carve to a grain to which we are sensitive in our everyday philosophising. The reason is that, unless we do so, we don’t get what we want from philosophical methodology. I argue that what we want is information that will aid us in formulating practical advice concerning how to do philosophy responsibly/well/better

Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance.

Overcoming drug resistance remains a key challenge to cure patients with acute and chronic B cell malignancies. Here, we describe a stromal cell-autonomous signaling pathway, which contributes to drug resistance of malignant B cells. We show that protein kinase C (PKC)-β-dependent signals from bone marrow-derived stromal cells markedly decrease the efficacy of cytotoxic therapies. Conversely, small-molecule PKC-β inhibitors antagonize prosurvival signals from stromal cells and sensitize tumor cells to targeted and nontargeted chemotherapy, resulting in enhanced cytotoxicity and prolonged survival in vivo. Mechanistically, stromal PKC-β controls the expression of adhesion and matrix proteins, required for activation of phosphoinositide 3-kinases (PI3Ks) and the extracellular signal-regulated kinase (ERK)-mediated stabilization of B cell lymphoma-extra large (BCL-XL) in tumor cells. Central to the stroma-mediated drug resistance is the PKC-β-dependent activation of transcription factor EB, regulating lysosome biogenesis and plasma membrane integrity. Stroma-directed therapies, enabled by direct inhibition of PKC-β, enhance the effectiveness of many antileukemic therapies.This work was funded by Cancer Research UK (CRUK; C49940/A17480). I.R. is a senior CRUK fellow. M.S.S is supported by the DFG through SCHM2440/7-1 and CRC1243 (A12). L.G. & O.W. received funding from CWCUK (grant 14-169) and GOSHCC (grant V2617). A.E. receives research grants from the Austrian Science Fund (FWF; Transcan I2795-B28 to A.E. (FIRE-CLL), DACH grants I3282-B26 and I1299-B21 (FOR2036) and a grant from the Paracelsus Medical University (PMU Grant E-13/18/091-EGF). S.S. receives funding from the DFG (SFB1074 , project B1), relevant to this work

Convergence of a common solution to broad ebolavirus neutralization by glycan cap directed human antibodies

Antibodies that target the glycan cap epitope on ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization is not well-understood. Here we present cryo-electron microscopy (cryo-EM) structures of several glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLD) to the glycan cap, which we name the MLD-anchor and cradle. Antibodies that bind to the MLD-cradle share common features, including the use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form beta-hairpin structures to mimic the MLD-anchor, disrupt MLD attachment, destabilize GP quaternary structure and block cleavage events required for receptor binding. Our results collectively provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies