Action representability of the category of internal groupoids

When $\mathbb C$ is a semi-abelian category, it is well known that the category $\mathsf{Grpd}(\mathbb C)$ of internal groupoids in $\mathbb C$ is again semi-abelian. The problem of determining whether the same kind of phenomenon occurs when the property of being semi-abelian is replaced by the one of being action representable (in the sense of Borceux, Janelidze and Kelly) turns out to be rather subtle. In the present article we give a sufficient condition for this to be true: in fact we prove that the category $\mathsf{Grpd}(\mathbb C)$ is a semi-abelian action representable algebraically coherent category with normalizers if and only if $\mathbb C$ is a semi-abelian action representable algebraically coherent category with normalizers. This result applies in particular to the categories of internal groupoids in the categories of groups, Lie algebras and cocommutative Hopf algebras, for instance.Comment: 13 page

Algebraic exponentiation and internal homology in general categories

Includes bibliographical references (p. 101-102).We study two categorical-algebraic concepts of exponentiation:(i) Representing objects for the so-called split extension functors in semi-abelian and more general categories, whose familiar examples are automorphism groups of groups and derivation algebras of Lie algebras. We prove that such objects exist in categories of generalized Lie algebras defined with respect to an internal commutative monoid in symmetric monoidal closed abelian category. (ii) Right adjoints for the pullback functors between D. Bourns categories of points. We introduce and study them in the situations where the ordinary pullback functors between bundles do not admit right adjoints in particular for semi-abelian, protomodular, (weakly) Maltsev, (weakly) unital, and more general categories. We present a number of examples and counterexamples for the existence of such right adjoints. We use the left and right adjoints of the pullback functors between categories of points to introduce internal homology and cohomology of objects in abstract categories

Infrared constraints on the dark mass concentration observed in the cluster Abell 1942

We present a deep H-band image of the region in the vicinity of the cluster Abell 1942 containing the puzzling dark matter concentration detected in an optical weak lensing study by Erben et al. (2000). We demonstrate that our limiting magnitude, H=22, would be sufficient to detect clusters of appropriate mass out to redshifts comparable with the mean redshift of the background sources. Despite this, our infrared image reveals no obvious overdensity of sources at the location of the lensing mass peak, nor an excess of sources in the I-H vs. H colour-magnitude diagram. We use this to further constrain the luminosity and mass-to-light ratio of the putative dark clump as a function of its redshift. We find that for spatially-flat cosmologies, background lensing clusters with reasonable mass-to-light ratios lying in the redshift range 0<z<1 are strongly excluded, leaving open the possibility that the mass concentration is a new type of truly dark object.Comment: 8 pages, 7 figures. MNRAS submitted (after referee revision

BBC Experiments in local radio broadcasting 1961-62

In the early 1960s, the BBC was given the opportunity to demonstrate that it had the skills and resources to create localized broadcasting, by organizing a series of experimental stations across the UK. Although the output was not heard publicly, the results were played to the Pilkington Committee on Broadcasting, who were deliberating about the future direction of radio and television. Using archival research, featuring contemporary BBC documents, this paper argues that these experimental stations helped senior managers at the BBC to harness technological innovation with changing attitudes in society and culture, thus enabling them to formulate a strategy that put the BBC in the leading position to launch local radio a few years later in 1967

Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep

siRNAs comprise a class of drugs that can be programmed to silence any target gene. Chemical engineering efforts resulted in development of divalent siRNAs (di-siRNAs), which support robust and long-term efficacy in rodent and nonhuman primate brains upon direct cerebrospinal fluid (CSF) administration. Oligonucleotide distribution in the CNS is nonuniform, limiting clinical applications. The contribution of CSF infusion placement and dosing regimen on relative accumulation, specifically in the context of large animals, is not well characterized. To our knowledge, we report the first systemic, comparative study investigating the effects of 3 routes of administration - intrastriatal (i.s.), i.c.v., and intrathecal catheter to the cisterna magna (ITC) - and 2 dosing regimens - single and repetitive via an implanted reservoir device - on di-siRNA distribution and accumulation in the CNS of Dorset sheep. CSF injections (i.c.v. and ITC) resulted in similar distribution and accumulation across brain regions. Repeated dosing increased homogeneity, with greater relative deep brain accumulation. Conversely, i.s. administration supported region-specific delivery. These results suggest that dosing regimen, not CSF infusion placement, may equalize siRNA accumulation and efficacy throughout the brain. These findings inform the planning and execution of preclinical and clinical studies using siRNA therapeutics in the CNS

Surgery for rheumatic heart disease in the Northern Territory, Australia, 1997-2016: what have we gained?

Background: Between 1964 and 1996, the 10-year survival of patients having valve replacement surgery for rheumatic heart disease (RHD) in the Northern Territory, Australia, was 68%. As medical care has evolved since then, this study aimed to determine whether there has been a corresponding improvement in survival. Methods: A retrospective study of Aboriginal patients with RHD in the Northern Territory, Australia, having their first valve surgery between 1997 and 2016. Survival was examined using Kaplan-Meier and Cox regression analysis. Findings: The cohort included 281 adults and 61 children. The median (IQR) age at first surgery was 31 (18-42) years; 173/342 (51%) had a valve replacement, 113/342 (33%) had a valve repair and 56/342 (16%) had a commissurotomy. There were 93/342 (27%) deaths during a median (IQR) follow-up of 8 (4-12) years. The overall 10-year survival was 70% (95% CI: 64% to 76%). It was 62% (95% CI: 53% to 70%) in those having valve replacement. There were 204/281 (73%) adults with at least 1 preoperative comorbidity. Preoperative comorbidity was associated with earlier death, the risk of death increasing with each comorbidity (HR: 1.3 (95% CI: 1.2 to 1.5), p50 mm Hg before surgery (HR 1.9 (95% CI: 1.2 to 3.1) p=0.007) were independently associated with death. Interpretation: Survival after valve replacement for RHD in this region of Australia has not improved. Although the patients were young, many had multiple comorbidities, which influenced long-term outcomes. The increasing prevalence of complex comorbidity in the region is a barrier to achieving optimal health outcomes

A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds.

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.This research was supported with funding from Cancer Research UK and from the European Union to the EUROCAN Network of Excellence (FP7; grant numnumber 260791). M.C. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sk1odowska-Curie grant agreement no. 660060 and was supported by the Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. R.N.B. is supported by the Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. S-J.S. is supported by the Wellcome Trust PhD Programme for Clinicians in Cambridge. A.Bruna, O.M.R., E.M., V.S., and C.C. are members of the EurOPDX Consortium. Weare very grateful for the generosity of all the patients that donated samples for implantation. We are also deeply indebted to all the staff (surgeons, pathologists, oncologists, theatre staff, and other ancillary personnel) at the Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Bio-repository Core Facilities for support during the execution of this project.This is the final version of the article. It first appeared from Elsevier at http://dx.doi.org/10.1016/j.cell.2016.08.041

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias

Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90−CD200+ and SIRPA+CD90−CD200−, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE)