Structural Characteristics and Stellar Composition of Low Surface Brightness Disk Galaxies

We present UBVI surface photometry of a sample of low surface brightness (LSB) disk galaxies. LSB disk galaxies are fairly well described as exponential disks with no preferred value for either scale length, central surface brightness, or rotational velocity. Indeed, the distribution of scale lengths is indistinguishable from that of high surface brightness spirals, indicating that dynamically similar galaxies (e.g., those with comparable Rv^2) exist over a large range in surface density. These LSB galaxies are strikingly blue. The complete lack of correlation between central surface brightness and color rules out any fading scenario. Similarly, the oxygen abundances inferred from HII region spectra are uncorrelated with color so the low metallicities are not the primary cause of the blue colors. While these are difficult to interpret in the absence of significant star formation, the most plausible scenario is a stellar population with a young mean age stemming from late formation and subsequent slow evolution. These properties suggest that LSB disks formed from low initial overdensities with correspondingly late collapse times.Comment: Astronomical Journal, in press 45 pages uuencoded postscript (368K) including 9 multipart figures also available by anonymous ftp @ ftp.ast.cam.ac.uk /pub/ssm/phot.uu CAP-30-210442962983742937

A Geographically-Restricted but Prevalent Mycobacterium tuberculosis Strain Identified in the West Midlands Region of the UK between 1995 and 2008

Background: We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Methodology/Principal Findings: Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95% CI = 4.56-17.87, p 65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95% CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.Conclusions/Significance: The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain

Reproducible, Ultra High-Throughput Formation of Multicellular Organization from Single Cell Suspension-Derived Human Embryonic Stem Cell Aggregates

Background: Human embryonic stem cells (hESC) should enable novel insights into early human development and provide a renewable source of cells for regenerative medicine. However, because the three-dimensional hESC aggregates [embryoid bodies (hEB)] typically employed to reveal hESC developmental potential are heterogeneous and exhibit disorganized differentiation, progress in hESC technology development has been hindered. Methodology/Principal Findings: Using a centrifugal forced-aggregation strategy in combination with a novel centrifugalextraction approach as a foundation, we demonstrated that hESC input composition and inductive environment could be manipulated to form large numbers of well-defined aggregates exhibiting multi-lineage differentiation and substantially improved self-organization from single-cell suspensions. These aggregates exhibited coordinated bi-domain structures including contiguous regions of extraembryonic endoderm- and epiblast-like tissue. A silicon wafer-based microfabrication technology was used to generate surfaces that permit the production of hundreds to thousands of hEB per cm 2. Conclusions/Significance: The mechanisms of early human embryogenesis are poorly understood. We report an ultra high throughput (UHTP) approach for generating spatially and temporally synchronised hEB. Aggregates generated in this manner exhibited aspects of peri-implantation tissue-level morphogenesis. These results should advance fundamental studies into early human developmental processes, enable high-throughput screening strategies to identify conditions tha

Macrosomia and large for gestational age in Asia:One size does not fit all

Macrosomia, usually defined as infant birth weight of >= 4000 g, does not consider gestational age, sex, or country/region-specific differences in mean birth weight and maternal body weight. This issue is particularly relevant for Asia, where 60% of the world's population lives, due to variations in maternal size and birth weights across populations. Large for gestational age (LGA), defined as birth weight > 90th centile, is a more sensitive measure as it considers gestational age and sex, though it is dependent on the choice of growth charts. We aimed to review reporting of macrosomia and LGA in Asia. We reviewed the literature on prevalence and risk of macrosomia and LGA in Asia over the last 29 years. Prevalence of macrosomia ranged from 0.5% (India) to 13.9% (China) while prevalence of LGA ranged from 4.3% (Korea) to 22.1% (China), indicating substantial variation in prevalence within and between Asian countries. High pre-pregnancy body mass index, excessive gestational weight gain, and impaired glucose tolerance conferred risk of macrosomia/LGA. Incidence of macrosomia and LGA varies substantially within and between Asian countries, as do the growth charts and definitions. The latter makes it impossible to make comparisons but suggests differences in intrauterine growth between populations. Reporting LGA, using standardized country/regional growth charts, would better capture the incidence of high birth weight and allow for comparison and identification of contributing factors. Better understanding of local drivers of excessive intrauterine growth could enable development of improved strategies for prevention and management of LGA

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Optical limiting in fullerene materials

Fullerene chemistry is booming, but how the chemical reactions affect fullerene's materials properties has seldom been studied. We have investigated optical limiting behavior of a series of fullerene derivatives, polymers, and glasses and have observed the following structure-property relationships for optical limiting in the fullerene materials: (i) The fullerene polymers with aromatic and chlorine moieties, i.e., C-60-containing polycarbonate (C-60-PC), polystyrene (C-60-PS), and poly(vinyl chloride) (C-60-PVC), limit the 8-ns pulses of 532-nm laser light more effectively than does the parent C-60; (ii) the fullerene polymers with carbonyl groups, i.e., C-60-containing CR-39 (C-60-CR-39) and poly(methyl methacrylate), (C-60-PMMA), do not enhance C-60's limiting power; and (iii) the aminated fullerene derivatives, i.e., HxC60(NBR), [R = -(CH2CH2O)(2)H (1), x = 11; -(CH2)(6)OH (2), x = 7; -cyclo-C6H11 (3), x = 11; -(CH2)(3)Si(OC2H5)(3) (4), x = 4], and their sol-gel glasses, i.e., 1-3/SiO2 (physical blending) and 4-SiO2 (chemical bonding), show complex limiting responses, with 4(-SiO2) performing consistently better than 1-3(/SiO2). The fullerene glasses are optically stable and their optical limiting properties remain unchanged after being subjected to continuous attack by the strong laser pulses for ca. 1 h

Synthesis and optical properties of fullerene-functionalized polycarbonates

Fullerenation of polycarbonate (PC) is achieved by direct reaction of C-60 with PC using AlCl3 as catalyst. Stirring a 1, 1, 2, 2-tetrachloroethane solution of C-60 and PC in the presence of AlCl3 under nitrogen at 140 degrees C for 24 h attached C-60 to the PC chains, yielding fullerenated PCs (C-60-PCs) with a C-60 content up to 2.16 wt \%. The C-60-PCs are soluble in tetrahydrofuran (THF) and chloroform, and IR, UV, and NMR analyses suggest that they possess the molecular structure HxC60(PC)(x) with x < 1 on the average. The C-60-PCs limit strong 532-nm optical pulses more effectively than the parent C-60. Light transmission spectra of the C-60-PC solutions red-shift with increasing concentration, with their cutoff wavelengths predictably tunable by simply changing their concentrations