A mutation in amino acid permease AAP6 reduces the amino acid content of the Arabidopsis sieve elements but leaves aphid herbivores unaffected

The aim of this study was to investigate the role of the amino acid permease gene AAP6 in regulating phloem amino acid composition and then to determine the effects of this altered diet on aphid performance. A genotype of Arabidopsis thaliana (L.) was produced in which the function of the amino acid permease gene AAP6 (At5g49630) was abolished. Plants homozygous for the insertionally inactivated AAP6 gene had a significantly larger mean rosette width than the wild type and a greater number of cauline leaves. Seeds from the aap6 mutant were also significantly larger than those from the wild-type plants. Sieve element (SE) sap was collected by aphid stylectomy and the amino acids derivatized, separated, and quantified using Capillary Electrophoresis with Laser Induced Fluorescence (CE-LIF). In spite of the large variation across samples, the total amino acid concentration of SE sap of the aap6 mutant plants was significantly lower than that of the wild-type plants. The concentrations of lysine, phenylalanine, leucine, and aspartic acid were all significantly lower in concentration in the aap6 mutant plants compared with wild-type plants. This is the first direct demonstration of a physiological role for an amino acid transporter in regulating SE composition in vivo. The amino acid availability in sieve element sap is thought to be the major limiting factor for aphid growth and reproduction. Despite the changes in their diet, the aphid Myzus persicae (Sulzer) displayed only small changes in feeding behaviour on mutant plants when measured using the Electronic Penetration Graph (EPG) technique. Salivation by the aphid into the SE (E1 phase) was increased on mutant plants but there was no significant effect on other feeding EPG behaviours, or in the rate of honeydew production. Consistent with the small effect on aphid feeding behaviour, there was only a small effect of reduced sieve element amino acid concentration on aphid reproduction. The data are discussed in relation to the regulation of phloem composition and the role of phloem amino acids in regulating aphid performance

Reduced signal for polygenic adaptation of height in UK Biobank

Several recent papers have reported strong signals of selection on European polygenic height scores. These analyses used height effect estimates from the GIANT consortium and replication studies. Here, we describe a new analysis based on the the UK Biobank (UKB), a large, independent dataset. We find that the signals of selection using UKB effect estimates are strongly attenuated or absent. We also provide evidence that previous analyses were confounded by population stratification. Therefore, the conclusion of strong polygenic adaptation now lacks support. Moreover, these discrepancies highlight (1) that methods for correcting for population stratification in GWAS may not always be sufficient for polygenic trait analyses, and (2) that claims of differences in polygenic scores between populations should be treated with caution until these issues are better understood.Editorial noteThis article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)

Ct threshold values, a proxy for viral load in community SARS-CoV-2 cases, demonstrate wide variation across populations and over time.

BACKGROUND: Information on SARS-CoV-2 in representative community surveillance is limited, particularly cycle threshold (Ct) values (a proxy for viral load). METHODS: We included all positive nose and throat swabs 26 April 2020 to 13 March 2021 from the UK's national COVID-19 Infection Survey, tested by RT-PCR for the N, S, and ORF1ab genes. We investigated predictors of median Ct value using quantile regression. RESULTS: Of 3,312,159 nose and throat swabs, 27,902 (0.83%) were RT-PCR-positive, 10,317 (37%), 11,012 (40%), and 6550 (23%) for 3, 2, or 1 of the N, S, and ORF1ab genes, respectively, with median Ct = 29.2 (~215 copies/ml; IQR Ct = 21.9-32.8, 14-56,400 copies/ml). Independent predictors of lower Cts (i.e. higher viral load) included self-reported symptoms and more genes detected, with at most small effects of sex, ethnicity, and age. Single-gene positives almost invariably had Ct > 30, but Cts varied widely in triple-gene positives, including without symptoms. Population-level Cts changed over time, with declining Ct preceding increasing SARS-CoV-2 positivity. Of 6189 participants with IgG S-antibody tests post-first RT-PCR-positive, 4808 (78%) were ever antibody-positive; Cts were significantly higher in those remaining antibody negative. CONCLUSIONS: Marked variation in community SARS-CoV-2 Ct values suggests that they could be a useful epidemiological early-warning indicator. FUNDING: Department of Health and Social Care, National Institutes of Health Research, Huo Family Foundation, Medical Research Council UK; Wellcome Trust

Chemically modified, non-anticoagulant heparin derivatives are potent galectin-3 binding inhibitors and inhibit circulating galectin-3-promoted metastasis

Concentrations of circulating galectin-3, a metastasis promoter, are greatly increased in cancer patients. Here we show that 2- or 6-de-O-sulfated, N-acetylated heparin derivatives are galectin-3 binding inhibitors. These chemically modified heparin derivatives inhibited galectin-3-ligand binding and abolished galectin-3-mediated cancer cell-endothelial adhesion and angiogenesis. Unlike standard heparin, these modified heparin derivatives and their ultra-low molecular weight sub-fractions had neither anticoagulant activity nor effects on E-, L- or P-selectin binding to their ligands nor detectable cytotoxicity. Intravenous injection of such heparin derivatives (with cancer cells pre-treated with galectin-3 followed by 3 subcutaneous injections of the derivatives) abolished the circulating galectin-3-mediated increase in lung metastasis of human melanoma and colon cancer cells in nude mice. Structural analysis using nuclear magnetic resonance and synchrotron radiation circular dichroism spectroscopies showed that the modified heparin derivatives bind to the galectin-3 carbohydrate-recognition domain. Thus, these chemically modified, non-anticoagulant, low-sulfated heparin derivatives are potent galectin-3 binding inhibitors with substantial potential as anti-metastasis/cancer drugs

Prefixes repel stress in reading aloud: Evidence from surface dyslexia

This study examined the importance of prefixes as sublexical cues for stress assignment during reading aloud English disyllabic words. In particular, we tested the hypothesis that prefixes repel stress (Rastle & Coltheart, 2000) by investigating the likelihood with which patients with surface dyslexia assign second-syllable stress to prefixed words. Five such patients were presented with three types of disyllabic words for reading aloud: 'regular' prefixed words with weak-strong stress pattern (e.g., remind); 'irregular' prefixed words with strong-weak stress pattern (e.g., reflex); and non-prefixed words with strong-weak stress pattern (e.g., scandal). Results showed that all five patients frequently regularized the strong-weak prefixed words by pronouncing them with second syllable stress. These regularization errors provide strong evidence for the functional role of prefixes in stress assignment during reading. Additional computational simulations using the rule-based algorithm for pronouncing disyllables developed by Rastle and Coltheart (2000) and the CDP++ model of reading aloud (Perry et al., 2010) allowed us to evaluate how these two opponent approaches to reading aloud fare in respect of the patient data.15 page(s

Brown Planthopper (N. lugens Stal) Feeding Behaviour on Rice Germplasm as an Indicator of Resistance

BACKGROUND: The brown planthopper (BPH) Nilaparvata lugens (Stal) is a serious pest of rice in Asia. Development of novel control strategies can be facilitated by comparison of BPH feeding behaviour on varieties exhibiting natural genetic variation, and then elucidation of the underlying mechanisms of resistance. METHODOLOGY/PRINCIPAL FINDINGS: BPH feeding behaviour was compared on 12 rice varieties over a 12 h period using the electrical penetration graph (EPG) and honeydew clocks. Seven feeding behaviours (waveforms) were identified and could be classified into two phases. The first phase involved patterns of sieve element location including non penetration (NP), pathway (N1+N2+N3), xylem (N5) [21] and two new feeding waveforms, derailed stylet mechanics (N6) and cell penetration (N7). The second feeding phase consisted of salivation into the sieve element (N4-a) and sieve element sap ingestion (N4-b). Production of honeydew drops correlated with N4-b waveform patterns providing independent confirmation of this feeding behaviour. CONCLUSIONS/SIGNIFICANCE: Overall variation in feeding behaviour was highly correlated with previously published field resistance or susceptibility of the different rice varieties: BPH produced lower numbers of honeydew drops and had a shorter period of phloem feeding on resistant rice varieties, but there was no significant difference in the time to the first salivation (N4-b). These qualitative differences in behaviour suggest that resistance is caused by differences in sustained phloem ingestion, not by phloem location. Cluster analysis of the feeding and honeydew data split the 12 rice varieties into three groups: susceptible, moderately resistant and highly resistant. The screening methods that we have described uncover novel aspects of the resistance mechanism (or mechanisms) of rice to BPH and will in combination with molecular approaches allow identification and development of new control strategies

Community prevalence of SARS-CoV-2 in England from April to November, 2020: results from the ONS Coronavirus Infection Survey

Background: Decisions about the continued need for control measures to contain the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on accurate and up-to-date information about the number of people testing positive for SARS-CoV-2 and risk factors for testing positive. Existing surveillance systems are generally not based on population samples and are not longitudinal in design. Methods: Samples were collected from individuals aged 2 years and older living in private households in England that were randomly selected from address lists and previous Office for National Statistics surveys in repeated cross-sectional household surveys with additional serial sampling and longitudinal follow-up. Participants completed a questionnaire and did nose and throat self-swabs. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time by use of dynamic multilevel regression and poststratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also assessed. The study is registered with the ISRCTN Registry, ISRCTN21086382. Findings: Between April 26 and Nov 1, 2020, results were available from 1 191 170 samples from 280 327 individuals; 5231 samples were positive overall, from 3923 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between April 26 and June 28, 2020, from 0·40% (95% credible interval 0·29–0·54) to 0·06% (0·04–0·07), followed by low levels during July and August, 2020, before substantial increases at the end of August, 2020, with percentages testing positive above 1% from the end of October, 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive for SARS-CoV-2 at the end of the first wave (April 26 to June 28, 2020), but not in the second wave (from the end of August to Nov 1, 2020). Age (young adults, particularly those aged 17–24 years) was an important initial driver of increased positivity rates in the second wave. For example, the estimated percentage of individuals testing positive was more than six times higher in those aged 17–24 years than in those aged 70 years or older at the end of September, 2020. A substantial proportion of infections were in individuals not reporting symptoms around their positive test (45–68%, dependent on calendar time. Interpretation: Important risk factors for testing positive for SARS-CoV-2 varied substantially between the part of the first wave that was captured by the study (April to June, 2020) and the first part of the second wave of increased positivity rates (end of August to Nov 1, 2020), and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the COVID-19 pandemic moving forwards. Funding: Department of Health and Social Care

Genome-Wide Association Study Identifies Single Nucleotide Polymorphism in DYRK1A Associated with Replication of HIV-1 in Monocyte-Derived Macrophages

Background: HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages. Methodology/Principal Findings: Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10-5). While the association was not genome-wide significant (p<1×10-7), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10-6). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048). Conclusions/Significance: These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo. © 2011 Bol et al

Population genomics applications for conservation: the case of the tropical dry forest dweller Peromyscus melanophrys

Recent advances in genomic sequencing have opened new horizons in the study of population genetics and evolution in non-model organisms. However, very few population genomic studies have been performed on wild mammals to understand how the landscape affects the genetic structure of populations, useful information for the conservation of biodiversity. Here, we applied a genomic approach to evaluate the relationship between habitat features and genetic patterns at spatial and temporal scales in an endangered ecosystem, the Tropical Dry Forest (TDF). We studied populations of the Plateau deer mouse Peromyscus melanophrys to analyse its genomic diversity and structure in a TDF protected area in the Huautla Mountain Range (HMR), Mexico based on 8,209 SNPs obtained through Genotyping-by-Sequencing. At a spatial scale, we found a significant signature of isolation-by-distance, few significant differences in genetic diversity indices among study sites, and no significant differences between habitats with different levels of human perturbation. At a temporal scale, while genetic diversity levels fluctuated significantly over time, neither seasonality nor disturbance levels had a significant effect. Also, outlier analysis revealed loci potentially under selection. Our results suggest that the population genetics of P. melanophrys may be little impacted by anthropogenic disturbances, or by natural spatial and temporal habitat heterogeneity in our study area. The genome-wide approach adopted here provides data of value for conservation planning, and a baseline to be used as a reference for future studies on the effects of habitat fragmentation and seasonality in the HMR and in TDF

Trends in postpartum hemorrhage in high resource countries: a review and recommendations from the International Postpartum Hemorrhage Collaborative Group

<p>Abstract</p> <p>Background</p> <p>Postpartum hemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Several recent publications have noted an increasing trend in incidence over time. The international PPH collaboration was convened to explore the observed trends and to set out actions to address the factors identified.</p> <p>Methods</p> <p>We reviewed available data sources on the incidence of PPH over time in Australia, Belgium, Canada, France, the United Kingdom and the USA. Where information was available, the incidence of PPH was stratified by cause.</p> <p>Results</p> <p>We observed an increasing trend in PPH, using heterogeneous definitions, in Australia, Canada, the UK and the USA. The observed increase in PPH in Australia, Canada and the USA was limited solely to immediate/atonic PPH. We noted increasing rates of severe adverse outcomes due to hemorrhage in Australia, Canada, the UK and the USA.</p> <p>Conclusion</p> <p><it>Key Recommendations</it></p> <p indent="1">1. Future revisions of the International Classification of Diseases should include separate codes for atonic PPH and PPH immediately following childbirth that is due to other causes. Also, additional codes are required for placenta accreta/percreta/increta.</p> <p indent="1">2. Definitions of PPH should be unified; further research is required to investigate how definitions are applied in practice to the coding of data.</p> <p indent="1">3. Additional improvement in the collection of data concerning PPH is required, specifically including a measure of severity.</p> <p indent="1">4. Further research is required to determine whether an increased rate of reported PPH is also observed in other countries, and to further investigate potential risk factors including increased duration of labor, obesity and changes in second and third stage management practice.</p> <p indent="1">5. Training should be provided to all staff involved in maternity care concerning assessment of blood loss and the monitoring of women after childbirth. This is key to reducing the severity of PPH and preventing any adverse outcomes.</p> <p indent="1">6. Clinicians should be more vigilant given the possibility that the frequency and severity of PPH has in fact increased. This applies particularly to small hospitals with relatively few deliveries where management protocols may not be defined adequately and drugs or equipment may not be on hand to deal with unexpected severe PPH.</p