Materials for stem cell factories of the future

The materials community is now identifying polymeric substrates that could permit translation of human pluripotent stem cells (hPSCs) from lab-based research to industrial scale biomedicine. Well defined materials are required to allow cell banking and to provide the raw material for reproducible differentiation into lineages for large scale drug screening programs and clinical use, wherein >1 billion cells for each patient are needed to replace losses during heart attack, multiple sclerosis and diabetes. Producing this number of cells for one patient is challenging and a rethink is needed to scalable technology with the potential to meet the needs of millions of patients a year. Here we consider the role of materials discovery, an emerging area of materials chemistry that is in a large part driven by the challenges posed by biologists to materials scientists1-4

AGRICULTURAL POLICY REFORM IN THE WTO: THE ROAD AHEAD

Agricultural trade barriers and producer subsidies inflict real costs, both on the countries that use these policies and on their trade partners. Trade barriers lower demand for trade partners' products, domestic subsidies can induce an oversupply of agricultural products which depresses world prices, and export subsidies create increased competition for producers in other countries. Eliminating global agricultural policy distortions would result in an annual world welfare gain of $56 billion. High protection for agricultural commodities in the form of tariffs continues to be the major factor restricting world trade. In 2000, World Trade Organization (WTO) members continued global negotiations on agricultural policy reform. To help policymakers and others realize what is at stake in the global agricultural negotiations, this report quantifies the costs of global agricultural distortions and the potential benefits of their full elimination. It also analyzes the effects on U.S. and world agriculture if only partial reform is achieved in liberalizing tariffs, tariff-rate quotas (limits on imported goods), domestic support, and export subsidies.Agricultural and Food Policy, International Relations/Trade,

diverse human vh antibody fragments with bio therapeutic properties from the crescendo mouse

Abstract We describe the 'Crescendo Mouse', a human VH transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA

Does self monitoring of blood glucose as opposed to urinalysis provide additional benefit in patients newly diagnosed with type 2 diabetes receiving structured education? The DESMOND SMBG randomised controlled trial protocol

BackgroundThe benefit of self-monitoring of blood glucose (SMBG) in people with type 2 diabetes on diet or oral agents other than sulphonylureas remains uncertain. Trials of interventions incorporating education about self-monitoring of blood glucose have reported mixed results. A recent systematic review concluded that SMBG was not cost-effective. However, what was unclear was whether a cheaper method of self-monitoring (such as urine glucose monitoring) could produce comparable benefit and patient acceptability for less cost.Methods/DesignThe DESMOND SMBG trial is comparing two monitoring strategies (blood glucose monitoring and urine testing) over 18 months when incorporated into a comprehensive self-management structured education programme. It is a multi-site cluster randomised controlled trial, conducted across 8 sites (7 primary care trusts) in England, UK involving individuals with newly diagnosed Type 2 diabetes.The trial has 80% power to demonstrate equivalence in mean HbA1c (the primary end-point) at 18 months of within ± 0.5% assuming 20% drop out and 20% non-consent. Secondary end-points include blood pressure, lipids, body weight and psychosocial measures as well as a qualitative sub-study.Practices were randomised to one of two arms: participants attend a DESMOND programme incorporating a module on self-monitoring of either urine or blood glucose. The programme is delivered by accredited educators who received specific training about equipoise. Biomedical data are collected and psychosocial scales completed at baseline, and 6, 12, and 18 months post programme. Qualitative research with participants and educators will explore views and experiences of the trial and preferences for methods of monitoring.DiscussionThe DESMOND SMBG trial is designed to provide evidence to inform the debate about the value of self-monitoring of blood glucose in people with newly diagnosed type 2 diabetes. Strengths include a setting in primary care, a cluster design, a health economic analysis, a comparison of different methods of monitoring while controlling for other components of training within the context of a quality assured structured education programme and a qualitative sub-study

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Multi-ancestry genome-wide study in &gt;2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P&lt;5×10 - 8 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care. </p

Provenance of Cretaceous through Eocene strata of the Four Corners region: Insights from detrital zircons in the San Juan Basin, New Mexico and Colorado

Cretaceous through Eocene strata of the Four Corners region provide an excellent record of changes in sediment provenance from Sevier thin-skinned thrusting through the formation of Laramide block uplifts and intra-foreland basins. During the ca. 125–50 Ma timespan, the San Juan Basin was flanked by the Sevier thrust belt to the west, the Mogollon highlands rift shoulder to the southwest, and was influenced by (ca. 75–50 Ma) Laramide tectonism, ultimately preserving a >6000 ft (>2000 m) sequence of continental, marginal-marine, and offshore marine sediments. In order to decipher the influences of these tectonic features on sediment delivery to the area, we evaluated 3228 U-Pb laser analyses from 32 detrital-zircon samples from across the entire San Juan Basin, of which 1520 analyses from 16 samples are newly reported herein. The detrital-zircon results indicate four stratigraphic intervals with internally consistent age peaks: (1) Lower Cretaceous Burro Canyon Formation, (2) Turonian (93.9–89.8 Ma) Gallup Sandstone through Campanian (83.6–72.1 Ma) Lewis Shale, (3) Campanian Pictured Cliffs Sandstone through Campanian Fruitland Formation, and (4) Campanian Kirtland Sandstone through Lower Eocene (56.0–47.8 Ma) San Jose Formation. Statistical analysis of the detrital-zircon results, in conjunction with paleocurrent data, reveals three distinct changes in sediment provenance. The first transition, between the Burro Canyon Formation and the Gallup Sandstone, reflects a change from predominantly reworked sediment from the Sevier thrust front, including uplifted Paleozoic sediments and Mesozoic eolian sandstones, to a mixed signature indicating both Sevier and Mogollon derivation. Deposition of the Pictured Cliffs Sandstone at ca. 75 Ma marks the beginning of the second transition and is indicated by the spate of near-depositional-age zircons, likely derived from the Laramide porphyry copper province of southern Arizona and southwestern New Mexico. Paleoflow indicators suggest the third change in provenance was complete by 65 Ma as recorded by the deposition of the Paleocene Ojo Alamo Sandstone. However, our new U-Pb detrital-zircon results indicate this transition initiated ∼8 m.y. earlier during deposition of the Campanian Kirtland Formation beginning ca. 73 Ma. This final change in provenance is interpreted to reflect the unroofing of surrounding Laramide basement blocks and a switch to local derivation. At this time, sediment entering the San Juan Basin was largely being generated from the nearby San Juan Mountains to the north-northwest, including uplift associated with early phases of Colorado mineral belt magmatism. Thus, the detrital-zircon spectra in the San Juan Basin document the transition from initial reworking of the Paleozoic and Mesozoic cratonal blanket to unroofing of distant basement-cored uplifts and Laramide plutonic rocks, then to more local Laramide uplifts.National Science Foundation (NSF grant EAR-1649254

The Privileged Normalization of Marijuana Use – an Analysis of Canadian Newspaper Reporting, 1997–2007

The objective of this study was to systematically examine predominant themes within mainstream media reporting about marijuana use in Canada. To ascertain the themes present in major Canadian newspaper reports, a sample (N&thinsp;=&thinsp;1999) of articles published between 1997 and 2007 was analyzed. Drawing from Manning’s theory of the symbolic framing of drug use within media, it is argued that a discourse of ‘privileged normalization’ informs portrayals of marijuana use and descriptions of the drug’s users. Privileged normalization implies that marijuana use can be acceptable for some people at particular times and places, while its use by those without power and status is routinely vilified and linked to deviant behavior. The privileged normalization of marijuana by the media has important health policy implications in light of continued debate regarding the merits of decriminalization or legalization and the need for public health and harm reduction approaches to illicit drug use