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The DANTE heat-treatment-simulation software package is available from Deformation Control Technology Inc. It is a finite-element-based tool that can be used to predict metallurgical phase transformations, dimensional changes and the stress state of steel hot forgings as a consequence of cooling practices. The surface and internal temperatures of a hot-forged shape change in accordance with surface heat loss.

The approach adopted for modeling the enclosure involved two basic steps. The first was to generate a model of a single crankshaft that accurately predicted the time-temperature history of a cooling crankshaft. The second was to use the single crankshaft model in conjunction with a cooling enclosure model, loaded with crankshafts, to evaluate the performance of enclosure designs.

The controlled cooling of a hot forging has several advantages over the antiquated practice of piling the forgings into a bin until the bin is full, then repeating the same uncontrolled filling of another bin until the forging run is completed. Repeatable cooling for each forging produces a consistent microstructure, hardness and residual-stress state in the parts as well as consistent dimensions at ambient temperature. If the cooling practice is controlled, these characteristics also can be controlled. The result is that finishing operations -- such as the machining of the part and minimization of distortion both during cooling and during machining -- can be optimized. For certain alloy steels, it is possible to use controlled cooling of the forging to achieve part properties without the need for additional heat treatment. The cooling rates provided by air passing over hot forgings can be simulated using CFD tools.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A -related disorder and raise possibilities for its treatment. eIF5A is critical for protein synthesis but has not yet been associated with congenital human disease. Here, the authors show that EIF5A variants cause a Mendelian disorder via reduced eIF5A-ribosome interactions and this phenotype is partially corrected by spermidine supplementation in yeast and zebrafish.

A small-molecule inhibitor of the Mediator-associated kinases CDK8 and CDK19 inhibits growth of acute myeloid leukaemia (AML) cells and induces upregulation of super-enhancer-associated genes with tumour suppressor and lineage-controlling functions; Mediator kinase inhibition therefore represents a promising therapeutic approach for AML. Anti-leukaemic effect of Mediator kinase inhibition Super-enhancers are large enhancers densely bound by transcription factors, the Mediator complex and chromatin regulators, which drive high expression of genes implicated in cell identity and disease. Matthew Shair and colleagues find that a small molecule inhibitor of the Mediator-associated kinase CDK8 inhibits growth of acute myeloid leukaemia (AML) cells and induces upregulation of super-enhancer-associated genes linked to tumour suppressor and lineage-controlling functions. This enhancer upregulation is surprising given that a bromodomain BRD4 inhibitor suppresses AML cell growth yet downregulates the super-enhancer-associated genes. Therefore the AML cells seem to depend on a precise dosage of super-enhancer-associated gene expression and CDK8 inhibition. Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes 1 , 2 . BRD4 and CDK7 are positive regulators of SE-mediated transcription 3 , 4 , 5 . By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo , and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA , IRF8 , IRF1 and ETV6 (refs 6 , 7 , 8 ). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

The practice of coiling aortopulmonary collaterals (APCs) before Fontan completion is controversial, and published data are limited. We sought to compare outcomes in subjects with and without pre-Fontan coil embolization of APCs using the Pediatric Heart Network Fontan Cross-Sectional Study database which enrolled survivors of prior Fontan palliation. We compared hospital length of stay after Fontan in 80 subjects who underwent APC coiling with 459 subjects who did not. Secondary outcomes included post-Fontan complications and assessment of health status and ventricular performance at cross-sectional evaluation (mean 8.6 ± 3.4 years after Fontan). Centers varied markedly in frequency of pre-Fontan APC coiling (range 0%-30% of subjects, P < .001). The coil group was older at Fontan ( P = .004) and more likely to have single right ventricular morphology ( P = .054) and pre-Fontan atrioventricular valve regurgitation ( P = .03). The coil group underwent Fontan surgery more recently ( P < .001), was more likely to have a prior superior cavopulmonary anastomosis ( P < .001), and more likely to undergo extracardiac Fontan connection ( P < .001) and surgical fenestration ( P < .001). In multivariable analyses, APC coiling was not associated with length of stay (hazard ratio for remaining in-hospital 0.91, 95% CI 0.70-1.18, P = .48) or postoperative complications, except more post-Fontan catheter interventions (hazard ratio 1.74, 95% CI 1.04-2.91, P = .03), primarily additional APC coils. The groups had similar outcomes at cross-sectional evaluation. Management of APCs before Fontan shows marked practice variation. We did not find an association between pre-Fontan coiling of APCs and shorter postoperative hospital stay or with better late outcomes. Prospective studies of this practice are needed.

Lambdoid craniosynostosis (CS) is a congenital anomaly resulting from premature fusion of the cranial suture between the parietal and occipital bones. Predominantly sporadic, it is the rarest form of CS and its genetic etiology is largely unexplored. Exome sequencing of 25 kindreds, including 18 parent–offspring trios with sporadic lambdoid CS, revealed a marked excess of damaging (predominantly missense) de novo mutations that account for ~ 40% of sporadic cases. These mutations clustered in the BMP signaling cascade (P = 1.6 × 10–7), including mutations in genes encoding BMP receptors (ACVRL1 and ACVR2A), transcription factors (SOX11, FOXO1) and a transcriptional co-repressor (IFRD1), none of which have been implicated in other forms of CS. These missense mutations are at residues critical for substrate or target sequence recognition and many are inferred to cause genetic gain-of-function. Additionally, mutations in transcription factor NFIX were implicated in syndromic craniosynostosis affecting diverse sutures. Single cell RNA sequencing analysis of the mouse lambdoid suture identified enrichment of mutations in osteoblast precursors (P = 1.6 × 10−6), implicating perturbations in the balance between proliferation and differentiation of osteoprogenitor cells in lambdoid CS. The results contribute to the growing knowledge of the genetics of CS, have implications for genetic counseling, and further elucidate the molecular etiology of premature suture fusion.

BackgroundProspective validation and comparison of the performance of nodule management protocols is limited. The aim of this study was to examine the performance of size and risk thresholds for assessing malignancy in solid nodules at baseline low-dose CT (LDCT) in a lung cancer screening (LCS) programme.MethodsThis was an observational study using data from the SUMMIT Study, a prospective longitudinal study investigating LDCT for LCS. Participants were 55–77 years old and met either the United States Preventative Services Task Force (2013) criteria or had a PLCOm2012 risk of ≥1.3%. LDCTs were reported using computer-aided detection software (Veolity, MeVIS) with semiautomated volumetry. Cancer outcomes were reported for solid nodules reported at baseline CT, with participants represented by the single largest solid nodule where more than one was present. Malignancy risk was stratified by long-axis diameter and volume using predefined size thresholds taken from British Thoracic Society and European Position statement guidelines: a 5/6 mm long axis diameter or 80/100 mm3 volume ‘rule out’ thresholds for low-risk nodules and ≥300 mm3 or ≥8 mm diameter with or without Brock score ≥10% ‘Rule in’ thresholds for high-risk nodules.Pearson’s χ2 test was used to calculate statistical significance for nominal variables, McNemar’s test for comparison of sensitivity/specificity and DeLong’ test for comparison of areas under the receiver operating characteristic curve (AUROC). Optimal thresholds were determined with Youden’s J statistic. Net benefit calculations were undertaken to compare the existing thresholds with 95% CIs calculated by bootstrap sampling.Results11 355 participants were included. Crude risk of malignancy in solid nodules at baseline LDCT was 3.8% (228/5929). Risk of malignancy in solid nodules <6 mm long-axis diameter or <100 mm3 volume was equivalent to that in participants with no nodules at baseline LDCT (0.88% and 0.84% vs 0.77%, p=0.4600 and p=0.7932, respectively). A <80 mm3 volume and <5 mm diameter ‘rule out’ threshold achieved sensitivity 86.8% and 93.4%, specificity 65.4% and 24.64%, and negative predictive value (NPV) 99.2% and 98.9%, respectively. The <80 mm3 volume threshold encompassed 63.3% of participants with a baseline solid nodule compared with 24.0% by the <5 mm diameter threshold.For nodules ≥8 mm diameter, the addition of a risk score (Brock ≥10%) was associated with a significant net benefit when compared with using size threshold alone by net effect analysis (31.24; 95% CI 26.19 to 35.89).ConclusionsSolid nodules <100 mm3 or <6 mm diameter are not associated with increased risk of lung cancer compared with participants with no nodules at baseline LDCT. Volumetric rule-out thresholds achieve equivalent NPV to long-axis diameter thresholds while encompassing significantly more participants, reducing the number of interval scans required.

Eligibility for lung cancer screening (LCS) requires assessment of lung cancer risk, based on smoking history alongside demographic and medical factors. Reliance on individual face-to-face eligibility assessment risks inefficiency and costliness. The SUMMIT Study introduced a telephone-based lung cancer risk assessment to guide invitation to face-to-face LCS eligibility assessment, which significantly increased the proportion of face-to-face attendees eligible for LCS. However, levels of agreement between phone screener and in-person responses were lower in younger individuals and minority ethnic groups. Telephone-based risk assessment is an efficient way to optimise selection for LCS appointments but requires further iteration to ensure an equitable approach.

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.