Hydrous silicate melts and the deep mantle H2O cycle

We report ab initio atomistic simulations of hydrous silicate melts under deep upper mantle to shallow lower mantle conditions and use them to parameterise density and viscosity across the ternary system MgO-SiO2-H2O (MSH). On the basis of phase relations in the MSH system, primary hydrous partial melts of the mantle have 40-50 mol% H2O. Our results show that these melts will be positively buoyant at the upper and lower boundaries of the mantle transition zone except in very iron-rich compositions, where ≳ 75% Mg is substituted by Fe. Hydrous partial melts will also be highly inviscid. Our results indicate that if melting occurs when wadsleyite transforms to olivine at 410 km, melts will be buoyant and ponding of melts is unexpected. Box models of mantle circulation incorporating the upward mobility of partial melts above and below the transition zone suggest that the upper mantle becomes efficiently hydrated at the expense of the transition zone such that large differences in H2O concentration between the upper mantle, transition zone and lower mantle are difficult to maintain on timescales of mantle recycling. The MORB source mantle with ∼0.02-0.04 wt% H2O may be indicative of the H2O content of the transition zone and lower mantle, resulting in a bulk mantle H2O content of the order 0.5 to 1 ocean mass, which is consistent with geochemical constraints and estimates of subduction ingassing

Rules, precursors and parameterization methodologies for topology optimized structural designs realized through additive manufacturing

Additive manufacturing, more commonly known as 3D printing is a rapidly developing, thoroughly novel means of producing complex, previously difficult to manufacture components. Slowly divorcing itself from previously held preconceptions of rapid prototyping and now capable of producing comparable structures from materials such as titanium and high strength nickel alloys, it is a means of manufacturing structures deemed too complex for existing fabrication techniques. Whilst free of conventional constraints, the unique intricacies of the manufacturing process can lead to the creation of factors, detrimental to production success. The research detailed within this paper demonstrates through example, how the orientation of a part prior to build can be optimized in order to significantly mitigate these effects and to maximize build economics. Furthermore the research details a new method for the combined assessment and tailored structural topology optimization of parts intended for production by specific additive manufacturing technologies

No widespread dissemination of Chlamydia trachomatis diagnostic-escape variants and the impact of Neisseria gonorrhoeae positivity on the Aptima Combo 2 assay

OBJECTIVES: A Finnish Chlamydia trachomatis (CT) new variant was detected in 2019 that escaped detection in the Hologic Aptima Combo 2 (AC2) assay due to a C1515T mutation in the CT 23S rRNA target region. Reflex testing of CT-negative/CT-equivocal specimens as well as those positive for Neisseria gonorrhoeae (NG) with the Hologic Aptima CT (ACT) assay was recommended to identify any CT variants. METHODS: From June to October 2019, specimens with discrepant AC2/ACT CT results were submitted to Public Health England and screened for detectable CT DNA using an inhouse real-time (RT)-PCR. When enough DNA was present, partial CT 23S rRNA gene sequencing was performed. Analysis of available relative light units and interpretative data was performed. RESULTS: A total of 317 discordant AC2/ACT specimens were collected from 315 patients. Three hundred were tested on the RT-PCR; 53.3% (n=160) were negative and 46.7% (n=140) were positive. Due to low DNA load in most specimens, sequencing was successful for only 36 specimens. The CT 23S rRNA wild-type sequence was present in 32 specimens, and two variants with C1514T or G1523A mutation were detected in four specimens from three patients. Of the discordant specimens with NG interpretation, 36.6% of NG-negative/CT-negative AC2 specimens had detectable CT DNA on the inhouse RT-PCR vs 53.3% of NG-positive/CT-negative specimens. CONCLUSIONS: No widespread dissemination of AC2 diagnostic-escape CT variants has occurred in England. We however identified the impact of NG positivity on the discordant AC2/ACT specimens; a proportion appeared due to NG positivity and the associated NG signal, rather than any diagnostic-escape variants or low DNA load. Several patients with gonorrhoea may therefore receive false-negative AC2 CT results. Single diagnostic targets and multiplex diagnostic assays have their limitations such as providing selection pressure for escape mutants and potentially reduced sensitivity, respectively. These limitations must be considered when establishing diagnostic pathways

Application of a genetic risk score to racially diverse type 1 diabetes populations demonstrates the need for diversity in risk-modeling

This is the final version of the article. Available from the publisher via the DOI in this record.Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb+), 790 first-degree relatives (≤1AAb+), 68 second-degree relatives (≤1 AAb+), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb+ relatives or controls (P < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 (P < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians (P < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS (P < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.Supported by grants from the National Institutes of Health P01 AI42288 (MAA), R01 DK106191 (TMB), UC4 DK104194 (CEM), and from the JDRF Career Development Award (2–2012–280 to TMB). RAO is supported by a Diabetes UK Harry Keen Fellowship. DJP is supported by the JDRF Postdoctoral Fellowship Award (2-PDF-2016-207-A-N)

Genetic parameters for social effects on survival in cannibalistic layers: Combining survival analysis and a linear animal model

<p>Abstract</p> <p>Background</p> <p>Mortality due to cannibalism in laying hens is a difficult trait to improve genetically, because censoring is high (animals still alive at the end of the testing period) and it may depend on both the individual itself and the behaviour of its group members, so-called associative effects (social interactions). To analyse survival data, survival analysis can be used. However, it is not possible to include associative effects in the current software for survival analysis. A solution could be to combine survival analysis and a linear animal model including associative effects. This paper presents a two-step approach (2STEP), combining survival analysis and a linear animal model including associative effects (LAM).</p> <p>Methods</p> <p>Data of three purebred White Leghorn layer lines from Institut de Sélection Animale B.V., a Hendrix Genetics company, were used in this study. For the statistical analysis, survival data on 16,780 hens kept in four-bird cages with intact beaks were used. Genetic parameters for direct and associative effects on survival time were estimated using 2STEP. Cross validation was used to compare 2STEP with LAM. LAM was applied directly to estimate genetic parameters for social effects on observed survival days.</p> <p>Results</p> <p>Using 2STEP, total heritable variance, including both direct and associative genetic effects, expressed as the proportion of phenotypic variance, ranged from 32% to 64%. These results were substantially larger than when using LAM. However, cross validation showed that 2STEP gave approximately the same survival curves and rank correlations as LAM. Furthermore, cross validation showed that selection based on both direct and associative genetic effects, using either 2STEP or LAM, gave the best prediction of survival time.</p> <p>Conclusion</p> <p>It can be concluded that 2STEP can be used to estimate genetic parameters for direct and associative effects on survival time in laying hens. Using 2STEP increased the heritable variance in survival time. Cross validation showed that social genetic effects contribute to a large difference in survival days between two extreme groups. Genetic selection targeting both direct and associative effects is expected to reduce mortality due to cannibalism in laying hens.</p

Mpox infection investigation using multiplexed syndromic diagnostics: Evaluation of an AusDiagnostics multiplexed tandem PCR (MT-PCR) syndromic panel

Background Detection of mpox virus during investigation of viral vesicular rash illness is required to identify mpox infection. Objectives This study evaluated the performance of a research-use-only (RUO) AusDiagnostics MT-PCR syndromic assay containing an mpox virus target. Methods The analytical specificity and limit of detection (LoD) of the AusDiagnostics MT-PCR mpox assay was verified using control material. Clinical performance was evaluated using anonymised residual nucleic acids extracted from swab specimens previously tested for mpox virus using a laboratory developed test (LDT). Residual nucleic acids were derived from consecutive sample panels collected during two periods in the 2022 mpox outbreak. Results The AusDiagnostics MT-PCR assay demonstrated an LoD of 35 input copies of mpox virus and correctly detected all relevant members of a specificity panel (n = 34). 175 residual nucleic acids were included in the study with a prevalence of mpox of 40.0% (95%CI 32.7–47.6). The AusDiagnostics MT-PCR mpox assay demonstrated an accuracy of 98.9% (95%CI 93.8–99.9), sensitivity of 94.2% (95%CI 85.2 – 98.1) and specificity of 100% (95%CI 95.6 -100), when compared to the LDT qPCR assay. The AusDiagnostics MT-PCR mpox assay detected additional vesicular rash pathogens in 26.8% samples. Co-detection with other vesicular rash pathogens was described in 12.8% of mpox virus detected samples Conclusions Performance of the RUO AusDiagnostics MT-PCR mpox assay was comparable to an LDT qPCR for the detection of mpox virus in nucleic acids extracted from swab specimens. The RUO AusDiagnostics MT-PCR mpox assay facilitated the simultaneous detection of additional infective etiologies of vesicular rash syndromes

Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus.

Specific differences in signaling and antiviral properties between the different Lambda-interferons, a novel group of interferons composed of IL-28A, IL-28B and IL-29, are currently unknown. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-28A and IL-29. Expression studies were performed by microarray analysis, quantitative PCR (qPCR), reporter gene assays and immunoluminometric assays. Signaling was analyzed by Western blot. HCV replication was measured in Huh-7 cells expressing subgenomic HCV replicon. All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IFN-λR1. Both, IL-28A and IL-29 activated STAT1 signaling. As revealed by microarray analysis, similar genes were induced by both cytokines in Huh-7 cells (IL-28A: 117 genes; IL-29: 111 genes), many of them playing a role in antiviral immunity. However, only IL-28A was able to significantly down-regulate gene expression (n = 272 down-regulated genes). Both cytokines significantly decreased HCV replication in Huh-7 cells. In comparison to liver biopsies of patients with non-viral liver disease, liver biopsies of patients with HCV showed significantly increased mRNA expression of IL-28A and IL-29. Moreover, IL-28A serum protein levels were elevated in HCV patients. In a murine model of viral hepatitis, IL-28 expression was significantly increased. IL-28A and IL-29 are up-regulated in HCV patients and are similarly effective in inducing antiviral genes and inhibiting HCV replication. In contrast to IL-29, IL-28A is a potent gene repressor. Both IFN-λs may have therapeutic potential in the treatment of chronic HCV

Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage

OBJECTIVE: Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH. METHODS: We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1-1, 2-1 or 2-2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3-6). RESULTS: We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume. CONCLUSION: The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study