Singular del Pezzo surfaces that are equivariant compactifications

We determine which singular del Pezzo surfaces are equivariant compactifications of G_a^2, to assist with proofs of Manin's conjecture for such surfaces. Additionally, we give an example of a singular quartic del Pezzo surface that is an equivariant compactification of a semidirect product of G_a and G_m.Comment: 14 pages, main result extended to non-closed ground field

Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

The β2–α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2–α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2–α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Highly Efficient Amplification of Chronic Wasting Disease Agent by Protein Misfolding Cyclic Amplification with Beads (PMCAb)

Protein misfolding cyclic amplification (PMCA) has emerged as an important technique for detecting low levels of pathogenic prion protein in biological samples. The method exploits the ability of the pathogenic prion protein to convert the normal prion protein to a proteinase K-resistant conformation. Inclusion of Teflon® beads in the PMCA reaction (PMCAb) has been previously shown to increase the sensitivity and robustness of detection for the 263 K and SSLOW strains of hamster-adapted prions. Here, we demonstrate that PMCAb with saponin dramatically increases the sensitivity of detection for chronic wasting disease (CWD) agent without compromising the specificity of the assay (i.e., no false positive results). Addition of Teflon® beads increased the robustness of the PMCA reaction, resulting in a decrease in the variability of PMCA results. Three rounds of serial PMCAb allowed detection of CWD agent from a 6.7×10−13 dilution of 10% brain homogenate (1.3 fg of source brain). Titration of the same brain homogenate in transgenic mice expressing cervid prion protein (Tg(CerPrP)1536+/− mice) allowed detection of CWD agent from the 10−6 dilution of 10% brain homogenate. PMCAb is, thus, more sensitive than bioassay in transgenic mice by a factor exceeding 105. Additionally, we are able to amplify CWD agent from brain tissue and lymph nodes of CWD-positive white-tailed deer having Prnp alleles associated with reduced disease susceptibility

Retinal Pathology of Pediatric Cerebral Malaria in Malawi

Introduction The causes of coma and death in cerebral malaria remain unknown. Malarial retinopathy has been identified as an important clinical sign in the diagnosis and prognosis of cerebral malaria. As part of a larger autopsy study to determine causes of death in children with coma presenting to hospital in Blantyre, Malawi, who were fully evaluated clinically prior to death, we examined the histopathology of eyes of patients who died and underwent autopsy. Methodology/Principal Findings Children with coma were admitted to the pediatric research ward, classified according to clinical definitions as having cerebral malaria or another cause of coma, evaluated and treated. The eyes were examined by direct and indirect ophthalmoscopy. If a child died and permission was given, a standardized autopsy was carried out. The patient was then assigned an actual cause of death according to the autopsy findings. The eyes were examined pathologically for hemorrhages, cystoid macular edema, parasite sequestration and thrombi. They were stained immunohistochemically for fibrin and CD61 to identify the components of thrombi, β-amyloid precursor protein to detect axonal damage, for fibrinogen to identify vascular leakage and for glial fibrillary acidic protein to detect gliosis. Sixty-four eyes from 64 patients were examined: 35 with cerebral malaria and 29 with comas of other causes. Cerebral malaria was distinguished by sequestration of parasitized erythrocytes, the presence and severity of retinal hemorrhages, the presence of cystoid macular edema, the occurrence and number of fibrin-platelet thrombi, the presence and amount of axonal damage and vascular leakage. Conclusions/Significance We found significant differences in retinal histopathology between patients who died of cerebral malaria and those with other diagnoses. These histopathological findings offer insights into the etiology of malarial retinopathy and provide a pathological basis for recently described retinal capillary non-perfusion in children with malarial retinopathy. Because of the similarities between the retina and the brain it also suggests mechanisms that may contribute to coma and death in cerebral malaria

Identifying lineage effects when controlling for population structure improves power in bacterial association studies

Bacteria pose unique challenges for genome-wide association studies because of strong structuring into distinct strains and substantial linkage disequilibrium across the genome1,2. Although methods developed for human studies can correct for strain structure3,4, this risks considerable loss-of-power because genetic differences between strains often contribute substantial phenotypic variability5. Here, we propose a new method that captures lineage-level associations even when locus-specific associations cannot be fine-mapped. We demonstrate its ability to detect genes and genetic variants underlying resistance to 17 antimicrobials in 3,144 isolates from four taxonomically diverse clonal and recombining bacteria: Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae. Strong selection, recombination and penetrance confer high power to recover known antimicrobial resistance mechanisms and reveal a candidate association between the outer membrane porin nmpC and cefazolin resistance in E. coli. Hence, our method pinpoints locus-specific effects where possible and boosts power by detecting lineage-level differences when fine-mapping is intractable

Acetate Kinase Isozymes Confer Robustness in Acetate Metabolism

Acetate kinase (ACK) (EC no: 2.7.2.1) interconverts acetyl-phosphate and acetate to either catabolize or synthesize acetyl-CoA dependent on the metabolic requirement. Among all ACK entries available in UniProt, we found that around 45% are multiple ACKs in some organisms including more than 300 species but surprisingly, little work has been done to clarify whether this has any significance. In an attempt to gain further insight we have studied the two ACKs (AckA1, AckA2) encoded by two neighboring genes conserved in Lactococcus lactis (L. lactis) by analyzing protein sequences, characterizing transcription structure, determining enzyme characteristics and effect on growth physiology. The results show that the two ACKs are most likely individually transcribed. AckA1 has a much higher turnover number and AckA2 has a much higher affinity for acetate in vitro. Consistently, growth experiments of mutant strains reveal that AckA1 has a higher capacity for acetate production which allows faster growth in an environment with high acetate concentration. Meanwhile, AckA2 is important for fast acetate-dependent growth at low concentration of acetate. The results demonstrate that the two ACKs have complementary physiological roles in L. lactis to maintain a robust acetate metabolism for fast growth at different extracellular acetate concentrations. The existence of ACK isozymes may reflect a common evolutionary strategy in bacteria in an environment with varying concentrations of acetate

A multilevel analysis of neighborhood and individual effects on individual smoking and drinking in Taiwan

<p>Abstract</p> <p>Background</p> <p>We assessed direct effects of neighborhood-level characteristics and interactive effects of neighborhood-level characteristics and individual socioeconomic position on adult smoking and drinking, after consideration of individual-level characteristics in Taiwan.</p> <p>Methods</p> <p>Data on individual sociodemographic characteristics, smoking, and drinking were obtained from Taiwan Social Change Survey conducted in 1990, 1995, and 2000. The overall response rate was 67%. A total of 5883 women and men aged over 20 living in 434 neighborhoods were interviewed. Participants' addresses were geocoded and linked with Taiwan census data for measuring neighborhood-level characteristics including neighborhood education, neighborhood concentration of elderly people, and neighborhood social disorganization. The data were analyzed with multilevel binomial regression models.</p> <p>Results</p> <p>Several interaction effects between neighborhood characteristics and individual socioeconomic status (SES) were found in multilevel analyses. Our results indicated that different neighborhood characteristics led to different interaction patterns. For example, neighborhood education had a positive effect on smoking for low SES women, in contrast to a negative effect on smoking for high SES women. This result supports the hypothesis of "relative deprivation," suggesting that poor people living in affluent neighborhoods suffer from relative deprivation and relative standing. On the other hand, neighborhood social disorganization has positive effects on drinking for low SES individuals, but not for high SES individuals. These interactive effects support the hypothesis of the double jeopardy theory, suggesting that living in neighborhoods with high social disorganization will intensify the effects of individual low SES.</p> <p>Conclusion</p> <p>The findings of this study show new evidence for the effects of neighborhood characteristics on individual smoking and drinking in Taiwan, suggesting that more studies are needed to understand neighborhood effects in Asian societies.</p

Conditional meta-analysis stratifying on detailed HLA genotypes identifies a novel type 1 diabetes locus around TCF19 in the MHC

The human leukocyte antigen (HLA) class II genes HLA-DRB1, -DQA1 and -DQB1 are the strongest genetic factors for type 1 diabetes (T1D). Additional loci in the major histocompatibility complex (MHC) are difficult to identify due to the region’s high gene density and complex linkage disequilibrium (LD). To facilitate the association analysis, two novel algorithms were implemented in this study: one for phasing the multi-allelic HLA genotypes in trio families, and one for partitioning the HLA strata in conditional testing. Screening and replication were performed on two large and independent datasets: the Wellcome Trust Case–Control Consortium (WTCCC) dataset of 2,000 cases and 1,504 controls, and the T1D Genetics Consortium (T1DGC) dataset of 2,300 nuclear families. After imputation, the two datasets have 1,941 common SNPs in the MHC, of which 22 were successfully tested and replicated based on the statistical testing stratifying on the detailed DRB1 and DQB1 genotypes. Further conditional tests using the combined dataset confirmed eight novel SNP associations around 31.3 Mb on chromosome 6 (rs3094663, p = 1.66 × 10−11 and rs2523619, p = 2.77 × 10−10 conditional on the DR/DQ genotypes). A subsequent LD analysis established TCF19, POU5F1, CCHCR1 and PSORS1C1 as potential causal genes for the observed association