Effect of molecular weight of amine end-modified poly(β-amino ester)s on gene delivery efficiency and toxicity

Amine end-modified poly(β-amino ester)s (PBAEs) have generated interest as efficient, biodegradable polymeric carriers for plasmid DNA (pDNA). For cationic, non-degradable polymers, such as polyethylenimine (PEI), the polymer molecular weight (MW) and molecular weight distribution (MWD) significantly affect transfection activity and cytotoxicity. The effect of MW on DNA transfection activity for PBAEs has been less well studied. We applied two strategies to obtain amine end-modified PBAEs varying in MW. In one approach, we synthesized four amine end-modified PBAEs with each at 15 different monomer molar ratios, and observed that polymers of intermediate length mediated optimal DNA transfection in HeLa cells. Biophysical characterization of these feed ratio variants suggested that optimal performance was related to higher DNA complexation efficiency and smaller nanoparticle size, but not to nanoparticle charge. In a second approach, we used preparative size exclusion chromatography (SEC) to obtain well-defined, monodisperse polymer fractions. We observed that the transfection activities of size-fractionated PBAEs generally increased with MW, a trend that was weakly associated with an increase in DNA binding efficiency. Furthermore, this approach allowed for the isolation of polymer fractions with greater transfection potency than the starting material. For researchers working with gene delivery polymers synthesized by step-growth polymerization, our data highlight the potentially broad utility of preparative SEC to isolate monodisperse polymers with improved properties. Overall, these results help to elucidate the influence of polymer MWD on nucleic acid delivery and provide insight toward the rational design of next-generation materials for gene therapy.Alnylam Pharmaceuticals (Firm)National Institutes of Health (U.S.) (Grant R01-EB000244-27)National Institutes of Health (U.S.) (Grant 5-R01-CA132091-04)National Science Foundation (U.S.). Graduate Research FellowshipNational Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F32-EB011867

A Deep, Wide-Field, and Panchromatic View of 47 Tuc and the SMC with HST: Observations and Data Analysis Methods

In HST Cycle 17, we imaged the well known globular star cluster 47 Tucanae for 121 orbits using ACS and both the UVIS and IR channels of WFC3 (GO-11677, PI - H. Richer). This unique data set was obtained to address many scientific questions that demand a very deep, panchromatic, and panoramic view of the cluster's stellar populations. In total, the program obtained over 0.75 Ms of imaging exposure time with the three HST cameras, over a time span of 9 months in 2010. The primary ACS field was imaged in the two broadband filters F606W and F814W filters, at 13 orientations, for all 121 orbits. The parallel WFC3 imaging provides a panchromatic (0.4 - 1.7 micron) and contiguous imaging swath over a 250 degree azimuthal range at impact radii of 6.5 -- 17.9 pc in 47 Tuc. This imaging totals over 60 arcmin^2 in area and utilizes the F390W and F606W broadband filters on WFC3/UVIS and the F110W and F160W broadband filters on WFC3/IR. In this paper, we describe the observational design of the new survey and one of the methods used to analyze all of the imaging data. This analysis combines over 700 full-frame images taken with the three HST cameras into a handful of ultra-deep, well-sampled combined images in each of the six filters. The results reveal unprecedented color-magnitude diagrams (CMDs) of the cluster extending to >30th magnitude in the optical, 29th magnitude in the UV, and 27th magnitude in the IR. The data set provides a characterization of the complete stellar populations of 47 Tuc, extending from the faintest hydrogen burning dwarfs through the main-sequence and giant branches, down to very cool white dwarf remnants in the cluster. The imaging also provides the deepest probe of the stellar populations of the background Small Magellanic Cloud (SMC) galaxy, resolving low mass main-sequence dwarfs with M < 0.2 Msun.Comment: Accepted for Publication in the Astronomical Journal. 23 pages, 13 figures, and 4 tables. Companion paper by K. Woodley is astro-ph/037477

Report of the Snowmass 2021 Topical Group on Lattice Gauge Theory

Lattice gauge theory continues to be a powerful theoretical and computational approach to simulating strongly interacting quantum field theories, whose applications permeate almost all disciplines of modern-day research in High-Energy Physics. Whether it is to enable precision quark- and lepton-flavor physics, to uncover signals of new physics in nucleons and nuclei, to elucidate hadron structure and spectrum, to serve as a numerical laboratory to reach beyond the Standard Model, or to invent and improve state-of-the-art computational paradigms, the lattice-gauge-theory program is in a prime position to impact the course of developments and enhance discovery potential of a vibrant experimental program in High-Energy Physics over the coming decade. This projection is based on abundant successful results that have emerged using lattice gauge theory over the years: on continued improvement in theoretical frameworks and algorithmic suits; on the forthcoming transition into the exascale era of high-performance computing; and on a skillful, dedicated, and organized community of lattice gauge theorists in the U.S. and worldwide. The prospects of this effort in pushing the frontiers of research in High-Energy Physics have recently been studied within the U.S. decadal Particle Physics Planning Exercise (Snowmass 2021), and the conclusions are summarized in this Topical Report.Comment: 57 pages, 1 figure. Submitted to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021). Topical Group Report for TF05 - Lattice Gauge Theor

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

Lattice QCD and Particle Physics

Contribution from the USQCD Collaboration to the Proceedings of the US Community Study on the Future of Particle Physics (Snowmass 2021).Comment: 27 pp. main text, 4 pp. appendices, 30 pp. reference

Dung removal increases under higher dung beetle functional diversity regardless of grazing intensification

Dung removal by macrofauna such as dung beetles is an important process for nutrient cycling in pasturelands. Intensification of farming practices generally reduces species and functional diversity of terrestrial invertebrates, which may negatively affect ecosystem services. Here, we investigate the effects of cattle-grazing intensification on dung removal by dung beetles in field experiments replicated in 38 pastures around the world. Within each study site, we measured dung removal in pastures managed with low- and high-intensity regimes to assess between-regime differences in dung beetle diversity and dung removal, whilst also considering climate and regional variations. The impacts of intensification were heterogeneous, either diminishing or increasing dung beetle species richness, functional diversity, and dung removal rates. The effects of beetle diversity on dung removal were more variable across sites than within sites. Dung removal increased with species richness across sites, while functional diversity consistently enhanced dung removal within sites, independently of cattle grazing intensity or climate. Our findings indicate that, despite intensified cattle stocking rates, ecosystem services related to decomposition and nutrient cycling can be maintained when a functionally diverse dung beetle community inhabits the human-modified landscape